research on cancer cells

Cancer Cell Biology Research

A dividing breast cancer cell.

Research in cancer cell biology seeks to define the biological basis underlying the differences between normal cells and cancerous cells. This includes studies of the fundamental mechanisms that drive pre-cancer states, oncogenic transformation, and that support tumor growth and behavior. Mechanistic understanding of this biology and the fundamental processes governing transformation, including the role of aging, gender, and ethnic disparities, are critical for identifying molecular targets for therapeutic or preventive interventions.

Research in this area is supported and directed by the Cancer Cell Biology Branch (CCBB) .

Cancer Cell Metabolism

Research in cancer cell metabolism focuses on altered cellular metabolic pathways that support the cancer phenotype, which is characterized by unchecked cell proliferation, resistance to metabolic and oxidative stress, evasion of programmed cell death, reduced dependence on growth factor signals, insensitivity to growth inhibitory signals, and resistance to therapeutic interventions.

Key research areas include:

Oncogenic reprogramming of cellular metabolism (e.g., the Warburg Effect, glutamine addiction, upregulated/deregulated fatty acid metabolism)
The links between protein translation, ribosome biogenesis, and metabolism
Tumor metabolite profiling and characterization
Regulation and mechanisms of nutrient, metabolic intermediate, and ion transport in cancer cells

Emerging areas in cancer metabolism include biological functions of metabolic intermediates, the molecular link between body homeostasis and cancer cell biology, mechanisms underlying the intersection between obesity and cancer, the metabolic plasticity of cancer cells, the mechanisms through which diet and fasting affect cancer initiation and maintenance, and the molecular mechanisms that lead to cancer cachexia.

Cancer Cell Stress Responses

Research in cancer cell stress responses focuses on the cell’s reaction to intrinsic and environmental stressors that determine whether a cell will die or adapt to survive. Examples of the types of stress included in this research area are oxidative stress, oncogenic stress, accumulation of unfolded or misfolded proteins, hypoxia, metal ions, chemotherapy, and inflammation.

Mechanisms of cell death (e.g., apoptosis, necrosis/necroptosis, autophagy, anoikis, ferroptosis, and other forms of programmed/non-programmed cell death)
Recycling of cellular components in response to stress (e.g., autophagy, mitophagy, lipophagy)
ER stress and the unfolded protein response
Exosome release as a mediator of cellular stress response and intercellular communications
Altered processing of growth factors and their associated receptors
Mechanisms of cellular control of toxic byproducts from biological processes (e.g., redox control)

Emerging areas relevant to this research include mechanisms of metal ions homeostasis, such as iron and copper, and their associated cellular targets and functions, and understanding the global effects of metal ions accumulation.

Organelle Biology

Research in the area of organelle biology investigates the mechanisms and role of dysregulated organelle biology in driving or supporting the cancer phenotype.

Dysregulation of organelle biogenesis and function (e.g., mitochondria, endoplasmic reticulum, Golgi, lysosomes, lipid droplets, peroxisomes, endosomes, and cilia)
Processing and trafficking of intracellular membranes and proteins
Endocytosis and endosome sorting and recycling
Interactions between nuclear-encoded oncogenic proteins and mitochondrial function
Role of cell organelles in cancer-associated phenotypes

Emerging areas relevant to this research include regulation of mitochondrial growth and division, energy-independent functions of mitochondria, and the intersection between organelle structure/morphology and the phenotypic state or function of cancer cells.

Cancer Cell Cycle Control

Dr. Sita Kugel Investigates the Biology of Pancreatic Cancer and Cholangiocarcinoma

Cell cycle dysregulation is a hallmark of cancer, and cell cycle components have been aggressively

targeted in chemotherapeutic strategies. Research in this area focuses on altered cell cycle regulation and its contribution to oncogenic transformation and tumor maintenance.

Characterization of factors that regulate cell cycle, mitosis, cytokinesis, centrosome duplication, and DNA replication in cancer cells
Alternative, kinase-independent functions of cell cycle regulators
Mechanisms that alter protein stability and function of cell cycle components in cancer cells
Understanding the biological effects of cell cycle inhibitors in tumors, either alone or in combination with other therapies

Emerging areas relevant to this research include the elucidation of nutrient-sensing cell cycle checkpoints, understanding mechanisms that allow for the bypass of cell cycle checkpoints, and exploration of combination therapies with CDK inhibitors for certain cancers.

Post-transcriptional Regulations Influencing Cancer

Research in this area investigates the wide-ranging mechanisms and functional effects of post-transcriptional regulations that affect the cancer phenotype.

Altered mechanisms and regulations of RNA stability, splicing, modifications, transport, and mRNA translation
Regulation and mechanisms of alternative splicing in cancer
The role of non-coding RNAs and RNA binding proteins in the regulation of splicing, modifications, transport, translation, and mRNA stability
Translation factors that act as oncogenes or tumor suppressors
Changes in protein maturation and stability, including diverse post-translation modifications (e.g., phosphorylation, acetylation, methylation, hydroxylation, ubiquitylation, sumoylation, neddylation, and glycosylation), as well as modifications of signaling effectors (e.g., promotors and drivers of tumorigenesis or cancer progression)

Emerging areas relevant to this research include the study of chemical modifications to RNAs and protein molecules, including writers, erasers, and readers of such modifications, that affect their stability, trafficking, RNA splicing and translation, and protein function, the development of novel technologies for efficient profiling of these modifications, and the interplay of different modifications and their alterations in cancer.

Basic Mechanisms of Cell Transformation

Research in this area includes mechanisms and effectors that govern the transition from normal cell to pre-cancer, early lesion, and cancer cell, as well as the identification of early biological events in transformation. Studies cover the role of tumor-initiating cells, field cancerization, and diverse signaling pathways governing cell fate determination and tumor formation. Research also examines the functions and regulations of oncogenes and tumor suppressor genes/proteins.

Functional and molecular characterization of oncogenes and tumor suppressors and their affected pathways
Oncogenic signal transduction and their rewiring
The biology of tumor-initiating cells and cancer stem cells
Role of developmental and cell differentiation programs in preneoplasia and cancer
Senescence as an oncogenic or tumor suppressive mechanism, the relationship between quiescence and senescence states, and the relationship between senescence, aging, and cancer

Emerging areas relevant to this research include understanding lineage affiliation of stem and progenitor cells and its role in oncogenesis, characterizing the actual cell targets for oncogenic transformation, and deciphering the functional effects of multiple mutations in normal cells and their role in transformation.

Biospecimen Resources to Support Cancer Biology Research

Research in this area includes the development of projects that encompass the collection, storage, processing, and dissemination of human biological specimens—including nucleic acids and tissue arrays—and associated data for studies of human cancer biology, particularly early events in cancer formation and pre-neoplasia.

Open access
Published: 26 November 2018

The 150 most important questions in cancer research and clinical oncology series: questions 94–101

Edited by Cancer Communications

Cancer Communications

Cancer Communications volume 38 , Article number: 69 ( 2018 ) Cite this article

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Since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer ) has published a series of important questions regarding cancer research and clinical oncology, to provide an enhanced stimulus for cancer research, and to accelerate collaborations between institutions and investigators. In this edition, the following 8 valuable questions are presented. Question 94. The origin of tumors: time for a new paradigm? Question 95. How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma? Question 96. Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor? Question 97. What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction? Question 98. Is high local concentration of metformin essential for its anti-cancer activity? Question 99. How can we monitor the emergence of cancer cells anywhere in the body through plasma testing? Question 100. Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells? Question 101. Is cell migration a selectable trait in the natural evolution of carcinoma?

Until now, the battle against cancer is still ongoing, but there are also ongoing discoveries being made. Milestones in cancer research and treatments are being achieved every year; at a quicker pace, as compared to decades ago. Likewise, some cancers that were considered incurable are now partly curable, lives that could not be saved are now being saved, and for those with yet little options, they are now having best-supporting care. With an objective to promote worldwide cancer research and even accelerate inter-countries collaborations, since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer ) has launched a program of publishing 150 most important questions in cancer research and clinical oncology [ 1 ]. We are providing a platform for researchers to freely voice-out their novel ideas, and propositions to enhance the communications on how and where our focus should be placed [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. In this edition, 8 valuable and inspiring questions, Question 94–101, from highly distinguished professionals from different parts of the world are presented. If you have any novel proposition(s) and Question(s), please feel free to contact Ms. Ji Ruan via email: [email protected].

Question 94: The origin of tumors: time for a new paradigm?

Background and implications.

“There is no worse blind man than the one who doesn’t want to see. There is no worse deaf man than the one who doesn’t want to hear. And there is no worse madman than the one who doesn’t want to understand.” —Ancient Proverb

In the past half-century, cancer biologists have focused on a dogma in which cancer was viewed as a proliferative disease due to mechanisms that activate genes (oncogenes) to promote cell proliferation or inactivate genes (tumor suppressor genes) to suppress tumor growth. In retrospect, these concepts were established based on functional selections, by using tissue culture (largely mouse NIH 3T3 cells) for the selection of transformed foci at the time when we knew virtually nothing about the human genome [ 14 ]. However, it is very difficult to use these genes individually or in combinations to transform primary human cells. Further, the simplified view of uncontrolled proliferation cannot explain the tumor as being a malignant organ or a teratoma, as observed by pathologists over centuries. Recently, the cancer genomic atlas project has revealed a wide variety of genetic alterations ranging from no mutation to multiple chromosomal deletions or fragmentations, which make the identification of cancer driver mutations very challenging in a background of such a massive genomic rearrangement. Paradoxically, this increase the evidences demonstrating that the oncogenic mutations are commonly found in many normal tissues, further challenging the dogma that genetic alteration is the primary driver of this disease.

Logically, the birth of a tumor should undergo an embryonic-like development at the beginning, similar to that of a human. However, the nature of such somatic-derived early embryo has been elusive. Recently, we provided evidence to show that polyploid giant cancer cells (PGCCs), which have been previously considered non-dividing, are actually capable of self-renewal, generating viable daughter cells via amitotic budding, splitting and burst, and capable of acquisition of embryonic-like stemness [ 15 , 16 , 17 ]. The mode of PGCC division is remarkably similar to that of blastomere, a first step in human embryogenesis following fertilization. The blastomere nucleus continuously divides 4–5 times without cytoplasmic division to generate 16–32 cells and then to form compaction/morulae before developing into a blastocyst [ 18 ]. Based on these data and similarity to the earliest stage of human embryogenesis, I propose a new theory that tumor initiation can be achieved via a dualistic origin, similar to the first step of human embryogenesis via the formation of blastomere-like cells, i.e. the activation of blastomere or blastomere-like cells which leads to the dedifferentiation of germ cells or somatic cells, respectively, which is then followed by the differentiation to generate their respective stem cells, and the differentiation arrest at a specific developmental hierarchy leading to tumor initiation [ 19 ]. The somatic-derived blastomere-like cancer stem cell follows its own mode of cell growth and division and is named as the giant cell cycle. This cycle includes four distinct but overlapping phases: the initiation, self-renewal, termination, and stability phases. The giant cell cycle can be tracked in vitro and in vivo due to their salient giant cell morphology (Fig. 1 ).

One mononucleated polyploid giant cancer cell (PGCC) in the background of regular size diploid cancer cells. The PGCC can be seen to be at least 100 times larger than that of regular cancer cells

This new theory challenges the traditional paradigm that cancer is a proliferative disease, and proposes that the initiation of cancer requires blastomere-like division that is similar to that of humans before achieving stable proliferation at specific developmental hierarchy in at least half of all human cancers. This question calls for all investigators in the cancer research community to investigate the role of PGCCs in the initiation, progression, resistance, and metastasis of cancer and to look for novel agents to block the different stages of the giant cell cycle.

The histopathology (phenotype) of cancers has been there all the time. It is just the theory of cancer origin proposed by scientists that changes from time to time. After all, trillions of dollars have been invested in fighting this disease by basing on its genetic origin in the past half-century, yet, little insight has been gained [ 14 ]. Here are two quotes from Einstein: “Insanity: doing the same thing over and over again expecting different results”, and “We cannot solve our problems with the same thinking we used when created them”.

In short, it is time to change our mindset and to start pursuing PGCCs, which we can observe under the microscope. But with very little understanding about these cells, it is time for a shift in paradigm.

Jinsong Liu.

Affiliation

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4095, USA.

Email address

[email protected]

Question 95: How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world with a dismal 5-year overall survival rate of less than 5%; which has not been significantly improved since the past decades. Although surgical resection is the only option for curative treatment of PDAC, only 15%–20% of patients with PDAC have the chance to undergo curative resection, leaving the rest with only palliative options in hope for increasing their quality of life; since they were already at unresectable and non-curative stages at their first diagnosis.

The lack of specific symptoms in the early-stage of PDAC is responsible for rendering an early diagnosis difficult. Therefore, more sensitive and specific screening methodologies for its early detection is urgently needed to improve its diagnosis, starting early treatments, and ameliorating prognoses. The diagnosis so far relies on imaging modalities such as abdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), and positron emission tomography (PET). One may propose to screen for pancreatic cancer in high-risk populations, which is highly recommended, however screening intervention for all the people is not a wise choice; when considering the relatively low prevalence of PDAC, and the difficulty for diagnosing it in its early stage [ 20 ].

Therefore, alternative diagnostic tools for early detection of PDAC are highly expected. Among the biomarkers currently used in clinical practice, carbohydrate antigen 19–9 (CA19–9) is among the most useful one for supporting the diagnosis of PDAC, but it is neither sufficiently sensitive nor specific for its early detection. Yachida et al. reported in 2010 that the initiating mutation in the pancreas occurs approximately two decades before the PDAC to start growing in distant organs [ 21 ], which indicates a broad time of the window of opportunity for the early detection of PDAC. With the advancement in next-generation sequencing technology, the number of reported studies regarding novel potential molecular biomarkers in bodily fluids including the blood, feces, urine, saliva, and pancreatic juice for early detection of PDAC has been increasing. Such biomarkers may be susceptible to detect mutations at the genetic or epigenetic level, identifying important non-coding RNA (especially microRNA and long non-coding RNA), providing insights regarding the metabolic profiles, estimating the tumor level in liquid biopsies (circulating free DNA, circulating tumor cells and exosomes), and so on.

Another approach to identifying biomarkers for the early detection of pancreatic cancer is using animal models. In spontaneous animal models of pancreatic cancer, such as Kras-mutated mouse models, it is expected that by high throughput analyses of the genetic/epigenetic/proteomic alterations, some novel biomarkers might be able to be identified. For instance, Sharma et al. reported in 2017 that the detection of phosphatidylserine-positive exosomes enabled the diagnosis of early-stage malignancies in LSL-Kras G12D , Cdkn2a lox/lox : p48 Cre and LSL-Kras G12d/+ , LSL-Trp R172H/+ , and P48 Cre mice [ 22 ].

These analyses in clinical samples or animal models hold the clues for the early detection of PDAC, however, further studies are required to validate their diagnostic performance. What’s most important, will be the lining-up of these identified prospective biomarkers, to validate their sensitivities and specificities. This will determine their potential for widespread clinical applicability, and hopefully, accelerate the early diagnosis of PDAC.

Mikiya Takao 1,2 , Hirotaka Matsuo 2 , Junji Yamamoto 1 , and Nariyoshi Shinomiya 2 .

1 Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan; 2 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.

E-mail address

[email protected]; [email protected]; [email protected]; [email protected]

Question 96: Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers, and nearly half of the patients had metastatic PDAC when they are initially diagnosed. When they are accompanied by metastatic tumors, unlike most solid cancer, PDAC cannot be cured with primary surgical resection alone [ 23 , 24 ]. Also, since PDAC has poor responses to conventional therapies, improvements in adjunctive treatment approach including chemo- and immuno-therapy are earnestly required. From this standpoint, recent results regarding the differences in the molecular evolution of pancreatic cancer subtypes provide a new insight into its therapeutic development [ 25 ], which may lead to the improvement of the prognosis of not only metastatic PDAC but also of locally advanced or recurrent PDAC.

In fact, new chemotherapeutic regimens such as the combination of gemcitabine with nab-paclitaxel and FOLFIRINOX have been reported to show improved prognosis despite a lack of examples of past successes in the treatment of patients with metastatic PDAC who had undergone R0 resection [ 26 ]. While many mutations including KRAS , CDKN2A , TP53, and SMAD4 are associated with pancreatic carcinogenesis, no effective molecular targeted drug has been introduced in the clinical setting so far. A recent report of a phase I/II study on refametinib, a MEK inhibitor, indicated that KRAS mutation status might affect the overall response rate, disease control rate, progression-free survival, and overall survival of PDAC in combination with gemcitabine [ 27 ].

While immunotherapy is expected to bring a great improvement in cancer treatment, until now, immune checkpoint inhibitors have achieved limited clinical benefit for patients with PDAC. This might be because PDAC creates a uniquely immunosuppressive tumor microenvironment, where tumor-associated immunosuppressive cells and accompanying desmoplastic stroma prevent the tumor cells from T cell infiltration. Recently reported studies have indicated that immunotherapy might be effective when combined with focal adhesion kinase (FAK) inhibitor [ 28 ] or IL-6 inhibitor [ 29 ], but more studies are required to validate their use in clinical practice.

As such, we believe that if the dynamic monitoring of drug sensitivity/resistance in the individual patients is coupled with precision treatment based on individualized genetics/epigenetics/proteomics alterations in the patients’ tumor, this could improve the treatment outcomes of PDAC.

Mikiya Takao 1,2 , Hirotaka Matsuo 2 , Junji Yamamoto 1 , and Nariyoshi Shinomiya 2.

Question 97: What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction?

Recently, cancer immunotherapy has shown great clinical benefit in multiple types of cancers [ 30 , 31 , 32 ]. It has provided new approaches for cancer treatment. However, it has been observed that only a fraction of patients respond to immunotherapy.

Much effort has been made to identify markers for immunotherapeutic response. Tumor mutation burden (TMB), mismatch repair (MMR) deficiency, PD-L1 expression, and tumor infiltration lymphocyte (TIL) have been found to be associated with an increased response rate in checkpoint blockade therapies. Unfortunately, a precise prediction is still challenging in this field. Moreover, when to stop the treatment of immunotherapy is an urgent question that remains to be elucidated.

In other words, there is no available approach to determine if a patient has generated a good immune response against the cancer after immunotherapy treatments. All of these indicate the complexity and challenges that reside for implementing novel man-induced cancer-effective immune response therapeutics. A variety of immune cells play collaborative roles at different stages to recognize antigens and eventually to generate an effective anti-cancer immune response. Given the high complexity of the immune system, a rational evaluation approach is needed to cover the whole process. Moreover, we need to perfect vaccine immunization and/or in vitro activation of T cells to augment the function of the immune system; particularly the formation of immune memory.

Edison Liu 1 , Penghui Zhou 2 , Jiang Li 2 .

1 The Jackson Laboratory, Bar Harbor, ME 04609, USA; 2 Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.

[email protected]; [email protected]; [email protected]

Question 98: Is high local concentration of metformin essential for its anti-cancer activity?

Metformin was approved as a first line of anti-diabetic drug since decades. Interestingly, the fact that clinical epidemiological studies have shown that metformin can reduce the risk of a variety of cancers stimulates considerable recognition to explore its anticancer activity.

Although the in vitro and in vivo experimental results have demonstrated that metformin can have some potential anti-tumor effects, more than 100 clinical trials did not achieve such desirable results [ 33 ]. We and others believe that the main problem resides in the prescribing doses used. For cancer treatment, a much higher dose may be needed for observing any anti-tumor activities, as compared to the doses prescribed for diabetics [ 34 , 35 , 36 ].

Further, if the traditional local/oral administration approach is favored, the prescribed metformin may not be at the required dose-concentration once it reaches the blood to have the effective anti-cancer activities. We, therefore, propose that intravesical instillation of metformin into the bladder lumen could be a promising way to treat for bladder cancer, at least. We have already obtained encouraging results both in vitro and in vivo experiments, including in an orthotopical bladder cancer model [ 36 , 37 ]. Now, we are waiting to observe its prospective clinical outcome.

Mei Peng 1 , Xiaoping Yang 2 .

1 Department of Pharmacy, Xiangya Hospital, Central South University. Changsha, Hunan 410083, P. R. China; 2 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.

[email protected]; [email protected]

Question 99: How can we monitor the emergence of cancer cells anywhere in the body through plasma testing?

The early detection of cancer is still a relentless worldwide challenge. The sensitivity and specificity of traditional blood tumor markers and imaging technologies are still to be greatly improved. Hence, novel approaches for the early detection of cancer are urgently needed.

The emergence of liquid biopsy technologies opens a new driveway for solving such issues. According to the definition of the National Cancer Institute of the United States, a liquid biopsy is a test done on a sample of blood to look for tumorigenic cancer cells or pieces of tumor cells’ DNA that are circulating in the blood [ 38 ]. This definition implies two main types of the current liquid biopsy: one that detects circulating tumor cells and the other that detects non-cellular material in the blood, including tumor DNA, RNA, and exosomes.

Circulating tumor cells (CTCs) are referred to as tumor cells that have been shed from the primary tumor location and have found their way to the peripheral blood. CTCs were first described in 1869 by an Australian pathologist, Thomas Ashworth, in a patient with metastatic cancer [ 39 ]. The importance of CTCs in modern cancer research began in the mid-1990s with the demonstration that CTCs exist early in the course of the disease.

It is estimated that there are about 1–10 CTCs per mL in whole blood of patients with metastatic cancer, even fewer in patients with early-stage cancer [ 40 ]. For comparison, 1 mL of blood contains a few million white blood cells and a billion erythrocytes. The identification of CTCs, being in such low frequency, requires some special tumoral markers (e.g., EpCAM and cytokeratins) to capture and isolate them. Unfortunately, the common markers for recognizing the majority of CTCs are not effective enough for clinical application [ 41 ]. Although accumulated evidences have shown that the presence of CTCs is a strong negative prognostic factor in the patients with metastatic breast, lung and colorectal cancers, detecting CTCs might not be an ideal branch to hold on for the hope of early cancer detection [ 42 , 43 , 44 , 45 ].

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the circulatory system, which is mainly derived from the tumor cell death through necrosis and/or apoptosis [ 46 ]. Given its origin, ctDNA inherently carries cancer-specific genetic and epigenetic aberrations, which can be used as a surrogate source of tumor DNA for cancer diagnosis and prognostic prediction. Ideally, as a noninvasive tumor early screening tool, a liquid biopsy test should be able to detect many types of cancers and provide the information of tumor origin for further specific clinical management. In fact, the somatic mutations of ctDNA in different types of tumor are highly variable, even in the different individuals with the same type of tumor [ 47 ]. Additionally, most tumors do not possess driver mutations, with some notable exceptions, which make the somatic mutations of ctDNA not suitable for early detection of the tumor.

Increased methylation of the promoter regions of tumor suppressor genes is an early event in many types of tumor, suggesting that altered ctDNA methylation patterns could be one of the first detectable neoplastic changes associated with tumorigenesis [ 48 ]. ctDNA methylation profiling provides several advantages over somatic mutation analysis for cancer detection including higher clinical sensitivity and dynamic range, multiple detectable methylation target regions, and multiple altered CpG sites within each targeted genomic region. Further, each methylation marker is present in both cancer tissue and ctDNA, whereas only a fraction of mutations present in cancer tissue could be detected in ctDNA.

In 2017, there were two inspiring studies that revealed the values of using ctDNA methylation analysis for cancer early diagnosis [ 49 , 50 ]. After partitioning the human genome into blocks of tightly coupled CpG methylation sites, namely methylation haplotype blocks (MHBs), Guo and colleagues performed tissue-specific methylation analyses at the MHBs level to accurately determine the tissue origin of the cancer using ctDNA from their enrolled patients [ 49 ]. In another study, Xu and colleagues identified a hepatocellular carcinoma (HCC) enriched methylation marker panel by comparing the HCC tissue and blood leukocytes from normal individuals and showed that methylation profiles of HCC tumor DNA and matched plasma ctDNA were highly correlated. In this study, after quantitative measurement of the methylation level of candidate markers in ctDNA from a large cohort of 1098 HCC patients and 835 normal controls, ten methylation markers were selected to construct a diagnostic prediction model. The proposed model demonstrated a high diagnostic specificity and sensitivity, and was highly correlated with tumor burden, treatment response, and tumor stage [ 50 ].

With the rapid development of highly sensitive detection methods, especially the technologies of massively parallel sequencing or next-generation sequencing (NGS)-based assays and digital PCR (dPCR), we strongly believe that the identification of a broader “pan-cancer” methylation panel applied for ctDNA analyses, probably in combination with detections of somatic mutation and tumor-derived exosomes, would allow more effective screening for common cancers in the near future.

Edison Liu 1 , Hui-Yan Luo 2 .

[email protected]; [email protected]

Question 100: Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells?

Though several anticancer agents are approved to treat different types of cancers, their full potentials have been limited due to the occurrence of drug resistance. Resistance to anticancer drugs develops by a variety of mechanisms, one of which is increased drug efflux by transporters. The ATP-binding cassette (ABC) family drug efflux transporter P-glycoprotein (P-gp or multi-drug resistance protein 1 [MDRP1]) has been extensively studied and is known to play a major role in the development of multi-drug resistance (MDR) to chemotherapy [ 51 ]. In brief, overexpressed P-gp efflux out a wide variety of anticancer agents (e.g.: vinca alkaloids, doxorubicin, paclitaxel, etc.), leading to a lower concentration of these drugs inside cancer cells, thereby resulting in MDR. Over the past three decades, researchers have developed several synthetic P-gp inhibitors to block the efflux of anticancer drugs and have tested them in clinical trials, in combination with chemotherapeutic drugs. But none were found to be suitable enough in overcoming MDR and to be released for marketing, mainly due to the side effects associated with cross-reactivity towards other ABC transporters (BCRP and MRP-1) and the inhibition of CYP450 drug metabolizing enzymes [ 52 , 53 ].

On the other hand, a number of phytochemicals have been reported to have P-gp inhibitory activity. Moreover, detailed structure–activity studies on these phytochemicals have delineated the functional groups essential for P-gp inhibition [ 53 , 54 ]. Currently, one of the phytochemicals, tetrandrine (CBT-1 ® ; NSC-77037), is being used in a Phase I clinical trial ( http://www.ClinicalTrials.gov ; NCT03002805) in combination with doxorubicin for the treatment of metastatic sarcoma. Before developing phytochemicals or their derivatives as P-gp inhibitors, they need to be investigated thoroughly for their cross-reactivity towards other ABC transporters and CYP450 inhibition, in order to avoid toxicities similar to the older generation P-gp inhibitors that have failed in clinical trials.

Therefore, the selectivity for P-gp over other drug transporters and drug metabolizing enzymes should be considered as important criterias for the development of phytochemicals and their derivatives for overcoming MDR.

Mohane Selvaraj Coumar and Safiulla Basha Syed.

Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.

[email protected]; [email protected]

Question 101: Is cell migration a selectable trait in the natural evolution of carcinoma?

The propensity of solid tumor malignancy to metastasize remains the main cause of cancer-related death, an extraordinary unmet clinical need, and an unanswered question in basic cancer research. While dissemination has been traditionally viewed as a late process in the progression of malignant tumors, amount of evidence indicates that it can occur early in the natural history of cancer, frequently when the primary lesion is still barely detectable.

A prerequisite for cancer dissemination is the acquisition of migratory/invasive properties. However, whether, and if so, how the migratory phenotype is selected for during the natural evolution of cancer and what advantage, if any, it may provide to the growing malignant cells remains an open issue. The answers to these questions are relevant not only for our understating of cancer biology but also for the strategies we adopt in an attempt of curbing this disease. Frequently, indeed, particularly in pharmaceutical settings, targeting migration has been considered much like trying “to shut the stable door after the horse has bolted” and no serious efforts in pursuing this aim has been done.

We argue, instead, that migration might be an intrinsic cancer trait that much like proliferation or increased survival confers to the growing tumor masses with striking selective advantages. The most compelling evidence in support for this contention stems from studies using mathematical modeling of cancer evolution. Surprisingly, these works highlighted the notion that cell migration is an intrinsic, selectable property of malignant cells, so intimately intertwined with more obvious evolutionarily-driven cancer traits to directly impact not only on the potential of malignant cells to disseminate but also on their growth dynamics, and ultimately provide a selective evolutionary advantage. Whether in real life this holds true remains to be assessed, nevertheless, work of this kind defines a framework where the acquisition of migration can be understood in a term of not just as a way to spread, but also to trigger the emergence of malignant clones with favorable genetic or epigenetic traits.

Alternatively, migratory phenotypes might emerge as a response to unfavorable conditions, including the mechanically challenging environment which tumors, and particularly epithelial-derived carcinoma, invariably experience. Becoming motile, however, may not per se being fixed as phenotypic advantageous traits unless it is accompanied or is causing the emergence of specific traits, including drug resistance, self-renewal, and survival. This might be the case, for example, during the process of epithelial-to-mesenchymal transition (EMT), which is emerging as an overarching mechanism for dissemination. EMT, indeed, may transiently equip individual cancer cells not only with migratory/invasive capacity but also with increased resistance to drug treatment, stemness potential at the expanse of fast proliferation.

Thus, within this framework targeting pro-migratory genes, proteins and processes may become a therapeutically valid alternative or a complementary strategy not only to control carcinoma dissemination but also its progression and development.

Giorgio Scita.

IFOM, The FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), School of Medicine, University of Milan, Via Festa del Perdono 7, 20122, Italy.

[email protected]

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Cancer Communications. The 150 most important questions in cancer research and clinical oncology series: questions 94–101. Cancer Commun 38 , 69 (2018). https://doi.org/10.1186/s40880-018-0341-9

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Tumor origin
Polyploid giant cancer cell
Pancreatic ductal adenocarcinoma
Liquid biopsy
Spontaneous animal model
Chemotherapy
Immunotherapy
Precision treatment
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Circulating tumor cell
Circulating tumor DNA
CpG methylation
Methylation haplotype block
Phytochemicals
P-Glycoprotein
Multi-drug resistance
P-Glycoprotein inhibitor
Epithelial-to-mesenchymal transition
Pro-migratory gene

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Cancer cells

This page has information about cancer cells and how they are different from normal body cells. You can read about

Features of normal cells

Normal body cells have a number of important features. They can:

reproduce when and where they need to
stick together in the right place in the body
self destruct when they become damaged or too old
become specialised (mature). This means they have a specific role to perform for example as a muscle cell or red blood cell.

Cancer cells are different to normal cells in various ways.

Cancer cells don't stop growing and dividing

Unlike normal cells, cancer cells don't stop growing and dividing when there are enough of them. So the cells keep doubling, forming a lump (tumour) that grows in size.

02_how_cancer_cells_keep_on_reproducing_to_form_a_tumour_1.svg

A tumour forms, made up of billions of copies of the original cancerous cell.

Cancers of blood cells don't form tumours for example leukaemias. But they make many abnormal blood cells that build up in the blood.

Cancer cells ignore signals from other cells

Cells send chemical signals to each other all the time. Normal cells obey signals that tell them when they have reached their limit. They will cause damage if they grow any further. But something in cancer cells stops the normal signalling system from working.

This 1 minute video shows how cancer cells send messages that tells other cells to grow and divide.

Cancer - When cells cause cancer by giving the wrong messages - Cancer Research UK

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View a transcript of the video .

Cancer cells don't stick together

Cancer cells can lose the molecules on their surface that keep normal cells in the right place. So they can break away from their neighbours.

34_diagram_showing_a_cancer_cell_which_has_lost_its_ability_to_stick_to_other_cells.svg

This helps to explain how cancer cells can spread to other parts of the body.

Read about how cancer can spread .

Cancer cells don't specialise

Unlike healthy cells, cancer cells don't carry on maturing or become so specialised. Cells mature so that they are able to carry out their function in the body. This process of maturing is called differentiation.

In cancer, the cells often reproduce very quickly and don't have a chance to mature. Because the cells aren't mature, they don't work properly. And because they divide quicker than usual, there's a higher chance that they will pick up more mistakes in their genes. This can make them even more immature so that they divide and grow even more quickly.

Cancer cells don't repair themselves or die

Normal cells can repair themselves if their genes become damaged. This is known as DNA repair. Cells self destruct if the damage is too bad. Scientists call this process apoptosis.

In cancer cells, the molecules that decide whether a cell should repair itself are faulty. For example, a protein called p53 usually checks if the cell can repair its genes, or if the cell should die. But many cancers have a faulty version of p53, so they don't repair themselves properly.

This leads to more problems. New gene faults or mutations can make cancer cells:

grow faster
spread to other parts of the body
resistant to treatment

Cancer cells can ignore the signals that tell them to self destruct. So they don't undergo apoptosis when they should. Scientists call this making cells immortal.

Cancer cells look different

Under a microscope, cancer cells may look very different from normal cells. Cancer cells:

are different sizes and some may be larger than normal while others are smaller
often have an abnormal shape
often have a nucleus (control centre) that looks abnormal

Find out about different types of cancer according to the cell type they start in

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Advancing Cancer Treatment

In many cancers studied thus far, a small population of cells called cancer stem cells self-renew to replenish the growing cancer. In order to eliminate the disease, it is these cells that chemotherapy must wipe out. Current treatments destroy cancer cells indiscriminately, draining the reservoir of cancer cells without specifically eliminating the cancer's source.

One important area of research at the institute involves learning whether all cancers have cancer stem cells. Stanford researchers are currently searching for stem cells that underlie cancers of the blood, breast, ovaries, lung, brain and bladder, among others -- making the institute the global epicenter of the cancer stem cell hunt.

Learning how cancer stem cells self-renew is the first step toward drugs that throw a wrench in the cancer propagation machine. One goal of the institute is to learn more about which proteins go awry in cancer stem cells in a broad range of cancer types. Eventually, this work could lead to new drugs that shut down these inappropriately active proteins.

For each type of cancer, it is also important to learn which genes are used in self-renewing adult stem cells compared with cancer stem cells in that same tissue. While both of these cells are capable of self-renewing, only the cancer cells go on to grow indefinitely and spread to other organs through the blood stream.

If researchers can learn which genes are mutated or used differently in the cancer cells, they can develop drugs to block that behavior without interfering with normal tissue-specific stem cells that replenish the brain, bone marrow, intestines, skin or other organs.

Research on cancer stem cells at the institute is being conducted in association with the Ludwig Center for Cancer Stem Cell Research and Medicine , which is a research collaboration between the institute and Stanford’s Comprehensive Cancer Center.

Learn about the many ways to support the institute for Stem Cell Biology and Regenerative Medicine

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Significant Research Advances Enabled by HeLa Cells

In 1952, HeLa cells became the first human cell line that could grow and divide endlessly in a laboratory, leading scientists to label these cells “immortal”. The immortality of HeLa cells contributed to their adoption across the world as the human cell line of choice for biomedical research. Though additional cells lines have been developed over the years, HeLa cells continue to be widely used to advance biomedical research and medicine.

The enduring use of HeLa cells in biomedical research is represented below through a timeline of events and scientific publications that describe research using HeLa cells. The timeline aims to show the role that HeLa cells have played in some of the major advances in fields such as cancer biology, infectious disease, fundamental microbiology and many others. The hyperlinked text provided in each entry provides the underlying sources for the advances and allows the reader to take a deeper look into the actual science. The events that were selected were based on the number of times researchers cited, or gave credit, to the publication(s) in which the events were described. Research involving HeLa cells has been described in more than 110,00 scientific publications. This staggering number makes it clear just how important these cells have been to research over the past six decades.

The versatility and power of HeLa cells have made them an essential laboratory tool that still continue to provide new clues about the basis of human health and disease.

Scientists track 'doubling' in origin of cancer cells

Working with human breast and lung cells, Johns Hopkins Medicine scientists say they have charted a molecular pathway that can lure cells down a hazardous path of duplicating their genome too many times, a hallmark of cancer cells.

The findings, published May 3 in Science , reveal what goes wrong when a group of molecules and enzymes trigger and regulate what's known as the "cell cycle," the repetitive process of making new cells out of the cells' genetic material.

The findings could be used to develop therapies that interrupt snags in the cell cycle, and have the potential to stop the growth of cancers, the researchers suggest.

To replicate, cells follow an orderly routine that begins with making a copy of their entire genome, followed by separating the genome copies, and finally, dividing the replicated DNA evenly into two "daughter" cells.

Human cells have 23 pairs of each chromosome -- half from the mother and half from the father, including the sex chromosomes X and Y -- or 46 total, but cancer cells are known to go through an intermediate state that has double that number -- 92 chromosomes. How this happens was a mystery.

"An enduring question among scientists in the cancer field is: How do cancer cell genomes get so bad?" says Sergi Regot, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine. "Our study challenges the fundamental knowledge of the cell cycle and makes us reevaluate our ideas about how the cycle is regulated."

Regot says cells that are stressed after copying the genome can enter a dormant, or senescent stage, and mistakenly run the risk of copying their genome again.

Generally and eventually, these dormant cells are swept away by the immune system after they are "recognized" as faulty. However, there are times, especially as humans age, when the immune system can't clear the cells. Left alone to meander in the body, the abnormal cells can replicate their genome again, shuffle the chromosomes at the next division, and a growing cancer begins.

In an effort to pin down details of the molecular pathway that goes awry in the cell cycle, Regot and graduate research assistant Connor McKenney, who led the Johns Hopkins team, focused on human cells that line breast ducts and lung tissue. The reason: These cells generally divide at a more rapid pace than other cells in the body, increasing the opportunities to visualize the cell cycle.

Regot's lab specializes in imaging individual cells, making it especially suited to spot the very small percentage of cells that don't enter the dormant stage and continue replicating their genome.

For this new study, the team scrutinized thousands of images of single cells as they went through cell division. The researchers developed glowing biosensors to tag cellular enzymes called cyclin dependent kinases (CDKs), known for their role in regulating the cell cycle.

They saw that a variety of CDKs activated at different times during the cell cycle. After the cells were exposed to an environmental stressor, such as a drug that disrupts protein production, UV radiation or so-called osmotic stress (a sudden change in water pressure around cells), the researchers saw that CDK 4 and CDK 6 activity decreased.

Then, five to six hours later, when the cells started preparations to divide, CDK 2 was also inhibited. At that point, a protein complex called the anaphase promoting complex (APC) was activated during the phase just before the cell pulls apart and divides, a step called mitosis.

"In the stressed environment in the study, APC activation occurred before mitosis, when it's usually been known to activate only during mitosis," says Regot.

About 90% of breast and lung cells leave the cell cycle and enter a quiet state when exposed to any environmental stressors.

In their experimental cells, not all of the cells went quiet.

The research team watched as about 5% to 10% of the breast and lung cells returned to the cell cycle, dividing their chromosomes again.

Through another series of experiments, the team linked an increase in activity of so-called stress activated protein kinases to the small percentage of cells that skirt the quiet stage and continue to double their genome.

Regot says there are ongoing clinical trials testing DNA-damaging agents with drugs that block CDK. "It's possible that the combination of drugs may spur some cancer cells to duplicate their genome twice and generate the heterogeneity that ultimately confers drug resistance," says Regot.

"There may be drugs that can block APC from activating before mitosis to prevent cancer cells from replicating their genome twice and prevent tumor stage progression," says Regot.

Other researchers who contributed to the study include Yovel Lendner, Adler Guerrero-Zuniga, Niladri Sinha, Benjamin Veresko and Timothy Aikin from Johns Hopkins.

Funding for the study was provided by the National Institutes of Health National Institute of General Medical Sciences (T32-GM007445, 1R35GM133499) and National Cancer Institute (1R01CA279546), the National Science Foundation and the American Cancer Society.

Lung Cancer
Biotechnology
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Journal Reference :

Connor McKenney et al. CDK4/6 activity is required during G2 arrest to prevent stress-induced endoreplication . Science , 2024 DOI: 10.1126/science.adi2421

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New mRNA vaccine for deadly brain cancer triggers a strong immune response

COVID-19 vaccine development paves way to a new class of cancer immunotherapy.

Glioblastoma brain cancer. Coloured computed tomography (CT) scan of a section through the brain (side-view) of an 84-year-old female patient with glioblastoma (dark, top).

For the first time, scientists have tested a messenger RNA (mRNA) vaccine in a patient with a deadly form of brain cancer — and it triggered a strong immune response.

The vaccine, which was described in a study published on May 1 in the journal Cell , was created by extracting genetic material called RNA from a tumor from a patient with glioblastoma, an aggressive type of cancer. The RNA was then replicated to make a vaccine from mRNA, which is a blueprint for what is inside every cell, including tumor cells.

"These results represent an exciting advance in next generation cancer therapies that leverage mRNA, the same class of medicines used in the COVID-19 vaccines ," Owen Fenton , an assistant professor of pharmacoengineering and molecular pharmaceutics at the University of North Carolina at Chapel Hill, who was not involved in the study, told Live Science in an email.

Moving at the speed of cancer

People have been developing cancer vaccines , or treatments that boost the body’s immune system attack against cancer cells, since the 1800s . However, cancer vaccines rarely mount an immune response strong enough to overcome the cancer.

Cancers mutate rapidly, so if doctors cut out a tumor and do a biopsy, the tumor itself may be different within 24 hours, said study senior author Dr. Elias Sayour , a pediatric oncologist and associate professor of neurosurgery at the University of Florida.

And by the time immune therapy begins, “the cancer is out of control now and so now the immune response is like a water gun in the face of a forest fire," Sayour told Live Science.

Up until now, cancer vaccines being tested have aimed to mount an immune response to a small number of molecular signatures from tumors from many different patients. In clinical trials, the vaccine material is often packaged into tiny lipid nanoparticles, but the trials typically only deliver a small number of particles and the vaccines themselves take months, if not years, to develop. However, cancer cells can adapt very quickly, figuring out ways to disable or block recognition by the local immune system.

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By isolating all the mRNA signatures in a patient’s tumor, designing a larger lipid nanoparticle and delivering more of the mRNA particles at once, Sayour and his team demonstrated an aggressive immune response specific to the patient’s tumor. And because mRNA can be isolated, amplified, and packaged for delivery within a matter of days, these tailored vaccines can be generated in about a month.

Sayour and other researchers hypothesize that the larger payload makes the nanoparticle look more dangerous to the body’s immune system, mounting a larger response.

And by using the vaccine technology developed against the COVID-19 virus, Sayour and his team were able to quickly create a vaccine specific to one patient’s tumor and train the patient’s immune system to specifically attack the tumor before it changed.

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"The beauty of RNA, which I think was proven in [the COVID-19] vaccines, is you can update them quickly and keep up against the spread of the pandemic . What if we could do the same in cancer?" said Sayour.

This novel therapy could likely be tailored to mount an immune response against other tumors in conjunction with existing therapies.

However, the study is still in very early days. As with all immunotherapies, there is a risk of an out-of-control immune response.

Sayour and his team will soon be treating more people in an expanded clinical trial to hone in on a treatment dosage that could minimize the harmful effects of a strong immune response and to see if the targeted mRNA vaccine works in other patients.

Jennifer Zieba earned her PhD in human genetics at the University of California, Los Angeles. She is currently a project scientist in the orthopedic surgery department at UCLA where she works on identifying mutations and possible treatments for rare genetic musculoskeletal disorders. Jen enjoys teaching and communicating complex scientific concepts to a wide audience and is a freelance writer for multiple online publications.

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Scientists track earliest cancer-triggering physical changes in cells

by Rachel Tompa, Yale University

In the early steps of cancer formation, timing matters

By the time cancer is diagnosed, a lot has already happened behind the scenes. Although cancers are classed into early and late stages for clinical purposes, even an "early" stage tumor is the result of many previous, undetectable cellular and molecular changes in the body.

Now, scientists at Yale School of Medicine (YSM) and their collaborators have caught a detailed glimpse of some of those earliest changes, using powerful, high-resolution microscopy to track the very first cancer -triggering physical changes in mouse skin cells.

By studying mice that carry a cancer-promoting mutation in their hair follicles, the scientists found that the earliest signs of cancer formation happen at a precise time and place in the growth of the hair follicles of the mouse skin cells. Further, they found that those precancerous changes can be blocked with a kind of drug known as an MEK inhibitor.

The team was led by Tianchi Xin, Ph.D., research scientist in genetics at YSM, and included Valentina Greco, Ph.D., Carolyn Walch Slayman Professor of Genetics at YSM and member of the Yale Cancer Center and Yale Stem Cell Center, and Sergi Regot, Ph.D., associate professor of molecular biology and genetics at Johns Hopkins School of Medicine.

They published the results of their research on April 30 in the journal Nature Cell Biology .

The scientists studied mice that develop cutaneous squamous cell carcinoma, the second most common type of human skin cancer. These mice were genetically engineered with a cancer-promoting mutation in a gene called KRAS, which is among the most commonly mutated oncogenes in human cancers. KRAS mutations have also been found to drive lung cancer, pancreatic cancer, and colorectal cancer, among others.

The early change that the scientists studied—the growth of a tiny, abnormal bump in the hair follicle —is classified as a pre-cancerous abnormality. "Understanding these early events could be helpful for us to actually design approaches to prevent the eventual formation of cancer," said Xin, who was first author on the study.

Although their study focused on skin cancer, the researchers believe the principles they discovered are likely to apply to the many other kinds of cancer driven by KRAS mutations because the basic genes and proteins involved are the same across different tumors.

Not just cell proliferation

As in humans, mouse hair follicles continually grow, shedding old hairs and forming new ones. Stem cells, which hold the capacity to develop into many other kinds of cells, drive much of this renewal cycle. Previous studies had found that KRAS mutations drive an increase in stem cell proliferation in hair follicles, and it was assumed this significant increase in the number of stem cells was responsible for the precancerous tissue disruption.

To test this assumption, the team used a specially engineered form of mutated KRAS that they could switch on at a specific time in the animals' hair follicle skin cells. Xin and his colleagues used a microscopy method known as intravital imaging, whose name refers to the technique's ability to image cells at high resolution in a living animal, and to label and follow individual stem cells in the animals.

When the KRAS mutation was triggered, all the stem cells proliferated faster, but the pre-cancerous bump only formed in one specific place in the hair follicle and in one stage in the growth cycle, meaning that the overall higher number of cells was likely not the whole story.

Switching on the KRAS mutation in hair follicles led the stem cells to proliferate faster, change their migration patterns, and divide in different directions from cells without the cancer-promoting mutation.

The mutation acts on a downstream protein known as ERK. Xin was able to observe real-time ERK activity in individual stem cells in live animals and discovered a specific change in that protein's activity triggered by the KRAS mutation. The researchers were also able to stop the formation of the pre-cancerous bump using an MEK inhibitor, which blocks ERK's activity.

The drug halted the mutation's effects on migration and cell orientation, but not on overall stem cell proliferation, implying that formation of the pre-cancerous condition is due to these first two changes, rather than to enhanced cell proliferation .

Precancer in context

Tracking the effects of an oncogenic mutation in real time, in a living animal, is the only way the researchers were able to uncover these principles. That is important because cancer does not form in a vacuum—it is highly dependent on its microenvironment to grow and sustain itself. The scientists also needed to track not only the behavior of individual cells, but the molecules within those cells.

"The way we've approached understanding these oncogenic events is really to connect across scale," Greco said. "The framework and approaches Dr. Xin used in collaboration with Dr. Regot allowed us to go down to molecular elements while connecting them to the scale of the cell and the tissue, in a way that gives us a resolution to these events that's so difficult to do outside a living animal."

Next, the researchers want to track the process for a longer time to see what happens after that initial bump forms. They also want to look at other cancer-promoting events like inflammation to see if the principles they discovered apply in other contexts.

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International Scholar Feature: Cancer immunotherapy research spans departments, continents

“Everyone has been impacted by cancer, directly or indirectly,” Lionel Apetoh said.

The Christopher Brown Professor of Immunology at the Indiana University School of Medicine, Apetoh speaks from experience.

His current research focuses on enhancing immune cells’ ability to combat cancer, a path he was inspired to pursue after losing his own mother to breast cancer.

Apetoh’s interest in immunology was sparked by his high school courses in his native France and continued through his undergraduate research at the University of Strasbourg. When he stumbled upon an advertisement for a Ph.D. program in oncology and immunology at the University of Paris, he saw it as a perfect fit for his interests, combining his passion for understanding the immune system’s role in disease with his desire to contribute to advancements in cancer treatment.

He was particularly drawn to understanding the communication between different cells of the immune system, recognizing its importance in the collaborative effort to fight disease. Through his Ph.D. research, he revealed a crucial insight: Cancer treatments such as chemotherapy and radiation don’t act alone in fighting cancer. Instead, they interact with the body’s immune response, which can either enhance or impede their effectiveness.

“A lot of what we’re doing is trying to answer the question, ‘Is there a way to predict what will happen when administering treatments?’” he said. “Can we predict how an individual will respond to treatment?”

By studying how the body’s pre-existing defense mechanisms interact with treatments, his research furthers collective efforts to fight cancer more effectively for every individual’s needs.

Apetoh’s academic journey has led him through various institutions. He has conducted research at Gustave Roussy, the largest cancer center in Europe; conducted post-doctoral research at Harvard Medical School; and established a lab in Inserm, a public research institute within the French Ministries of Health and Research.

He is continuing his public-institution research legacy at the IU Melvin and Bren Simon Comprehensive Cancer Center’s Brown Center for Immunotherapy , which translates IU research into clinical trials targeting multiple myeloma and triple negative breast cancer — two conditions that often resist standard cancer treatment.

Apetoh’s research at the Brown Center is part of his ongoing investigation on T-cells, which are pivotal players in the body’s immune response against disease, notably cancer. He and his fellow researchers are trying to improve the efficacy and power of these white blood cells to make chemotherapy more effective and to better predict how well a treatment will work on different patients.

His findings contribute valuable insights to enhance the efficacy of promising cancer vaccines. In their collaborative efforts, Apetoh’s research in fortifying immune cells to combat cancer intersects with the pioneering work of IU School of Medicine professor Pravin Kaumaya , a renowned expert in cancer vaccine development and director of the Immuno-Oncology and Vaccine Immunotherapy Laboratory in the Brown Center.

Kaumaya’s innovative vaccines are designed to instruct the immune system to target specific proteins, a strategy that aligns closely with Apetoh’s investigations into enhancing immune cell communication and precision targeting against cancer.

Apetoh is deeply committed to engaging with both local and global communities, fostering collaboration between scientists and advocating for scientific outreach, including visits to high schools to explain research in layman’s terms.

“Collaboration is key across departments,” Apetoh said. “For instance, findings from immunology can directly benefit colleagues in neuroscience. At IU, research in any department can positively impact every other department.”

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Researchers develop ‘founding document’ on synthetic cell development.

Tara Friesen

A scientist is looking through a microscope while backlit by a red image on a computer screen. Synthetic cell development could lead researchers to new developments in food and medical sciences and a better understanding of the origins of life on Earth.

Cells are the fundamental units of life, forming the variety of all living things on Earth as individual cells and multi-cellular organisms. To better understand how cells perform the essential functions of life, scientists have begun developing synthetic cells – non-living bits of cellular biochemistry wrapped in a membrane that mimic specific biological processes.

The development of synthetic cells could one day hold the answers to developing new ways to fight disease, supporting long-duration human spaceflight, and better understanding the origins of life on Earth.

In a paper published recently in ACS Synthetic Biology , researchers outline the potential opportunities that synthetic cell development could unlock and what challenges lie ahead in this groundbreaking research. They also present a roadmap to inspire and guide innovation in this intriguing field.

“The potential for this field is incredible,” said Lynn Rothschild, the lead author of the paper and an astrobiologist at NASA’s Ames Research Center in California’s Silicon Valley. “It’s a privilege to have led this group in forming what we envision will be a founding document, a resource that will spur this field on.”

Synthetic cell development could have wide ranging benefits to humanity. Analyzing the intricacies that go in to building a cell could guide researchers to better understand how cells first evolved or open the door to creating new forms of life more capable of withstanding harsh environments like radiation or freezing temperatures.

These innovations could also lead to advancements in food and medical sciences – creating efficiencies in food production, detecting contaminants in manufacturing, or developing novel cellular functions that act as new therapies for chronic diseases and even synthetic organ transplantation.

Building synthetic cells could also answer some of NASA’s biggest questions about the possibility of life beyond Earth.

“The challenge of creating synthetic cells informs whether we’re alone in the universe,” said Rothschild. “We’re starting to develop the skills to not just create synthetic analogs of life as it may have happened on Earth but to consider pathways to life that could form on other planets.”

As research continues on synthetic cell development, Rothschild sees opportunities where it could expand our understanding of the complexities of natural life.

“Life is an amazing thing. We use the capabilities of cells all the time – we build houses with wood, we use leather in our shoes, we breathe oxygen. Life has amazing precision, and if you can harness it, it’s unbelievable what we could accomplish.”

For news media :

Members of the news media interested in covering this topic should reach out to the NASA Ames newsroom .

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Review Article
Published: 20 May 2020

A guide to cancer immunotherapy: from T cell basic science to clinical practice

Alex D. Waldman ORCID: orcid.org/0000-0002-2016-6118 1 , 2 ,
Jill M. Fritz 1 , 2 &
Michael J. Lenardo ORCID: orcid.org/0000-0003-1584-468X 1 , 2

Nature Reviews Immunology volume 20 , pages 651–668 ( 2020 ) Cite this article

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Cancer immunotherapy
Drug discovery

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

Cytotoxic CD8+ T cells in cancer and cancer immunotherapy

Revisiting the role of CD4+ T cells in cancer immunotherapy—new insights into old paradigms

New immune cell engagers for cancer immunotherapy

Introduction.

The idea to deploy the immune system as a tool to treat neoplastic disease originated in the nineteenth century 1 . Wilhelm Busch and Friedrich Fehleisen were the first to describe an epidemiological association between immune status and cancer. They noticed spontaneous regression of tumours following the development of erysipelas, a superficial skin infection most commonly caused by Streptococcus pyogenes 1 . Later, William Coley, often called the ‘Father of Cancer Immunotherapy’, retrospectively demonstrated that erysipelas was associated with a better outcome in patients with sarcoma 2 . With hopes of prospectively verifying his epidemiological evidence, Coley treated patients with cancer with extracts of heat-inactivated S. pyogenes and Serratia marcescens to boost immunity 3 . This extract, termed ‘Coley’s toxins’, possessed potent immunostimulatory properties and achieved favourable responses in various cancers 2 . However, lack of scientific rigour and reproducibility, in concert with the discovery of radiotherapy and chemotherapeutic agents, prevented treatment with ‘Coley’s toxins’ from becoming standard practice 1 .

The concept of cancer immunotherapy resurfaced in the twentieth century and made significant headway with the advent of new technology. In 1909, Paul Ehrlich hypothesized that the human body constantly generates neoplastic cells that are eradicated by the immune system 3 . Lewis Thomas and Sir Frank Macfarlane Burnet independently conceived the ‘cancer immunosurveillance’ hypothesis, stating that tumour-associated neoantigens are recognized and targeted by the immune system to prevent carcinogenesis in a manner similar to graft rejection 1 . Productive immune responses following tumoural adoptive transfer in mice 4 and clinical reports of spontaneous regression of melanoma in patients with concomitant autoimmune disease 5 provided additional evidence supporting this hypothesis, although a unifying mechanism was elusive. The advent of knockout mouse models provided the necessary technology to experimentally demonstrate a link between immunodeficiency and cancer 6 . Additional molecular and biochemical advances led to the identification of tumour-specific immune responses 7 . This provided unequivocal evidence that the immune system, in particular T cells (see Box 1 and Fig. 1 ), was capable of waging war on cancer tissue 7 . Cancer immunotherapy has now revolutionized the field of oncology by prolonging survival of patients with rapidly fatal cancers. The number of patients eligible for immune-based cancer treatments continues to skyrocket as these therapies position themselves as the first line for many cancer indications. Novel treatment combinations and newly identified druggable targets will only expand the role of immunotherapy in the treatment of cancer in the decades to come.

Resting T cells become activated after stimulation by cognate antigen in the context of an antigen-presenting cell and co-stimulatory signals. Activated T cells produce and consume proliferative/survival cytokines, for example, IL-2, IL-4 and IL-7, and begin to expand in number. If CD4 + CD25 + regulatory T (T reg ) cells are present, they can deprive the cycling T cells of proliferative/survival cytokines, especially IL-2, causing them to undergo apoptosis. Once cells are proliferating rapidly, they have different fates depending on their environment. If they receive acute strong antigenic stimulation, especially if it is encountered repeatedly, the cells will undergo restimulation-induced cell death. By contrast, if they receive chronic weak antigenic stimulation, the cells will survive but become reprogrammed into a specific unresponsive transcriptional state known as ‘T cell exhaustion’. Finally, as the antigen and cytokine stimulation diminishes as the immune response wanes, usually once the pathogen has been cleared, cytokine withdrawal can occur passively to contract the expanded population of antigen-specific T cells. A small fraction of cells will be reprogrammed to enter a ‘memory’ phenotype, and this differentiation step is facilitated by IL-7 and IL-15. Memory T cells will continue to persist in the immune system and form the basis of anamnestic responses. In these regulatory processes, T cell death usually takes the form of apoptosis.

In this Review, we emphasize the role of T cells in modern cancer immunotherapies and discuss three different categories of immunotherapeutic approaches to treat cancer: immune checkpoint blockade, an approach that is designed to ‘unleash’ powerful T cell responses; adoptive cellular therapies, which are based on the infusion of tumour-fighting immune cells into the body; and cancer vaccines, which can be designed to have either prophylactic or therapeutic activity. Finally, we introduce some of the emerging targets and approaches in cancer immunotherapy.

Box 1 T cell function, development, activation and fate

The 1960s represented a period of enlightenment within the field of immunology because two major subtypes of lymphocytes, B lymphocytes and T lymphocytes, were characterized 264 , 265 . This was recognized by the 2019 Lasker Award for Basic Science, awarded for the pioneering work by Jacques A. F. P. Miller and Max Dale Cooper that defined the key roles of T cells and B cells in adaptive immunity. B cells recognize circulating antigen in its native form and respond by secreting protective antibodies 266 . By contrast, T cells recognize peptide antigens, derived from proteins degraded intracellularly, that are loaded onto cell surface MHC molecules, a process called antigen presentation. Two broad classes of T cells that have distinct effector mechanisms are delineated by the expression of either the CD4 or CD8 co-receptor: CD4 + T cells detect antigen in the context of MHC class II molecules and orchestrate the adaptive arm of the immune system by producing cytokines with chemotactic, pro-inflammatory and immunoprotective properties 267 . At least one CD4 + T cell subclass, CD4 + CD25 + regulatory T cells, dampens the immune response following challenge 268 . CD8 + T cells detect antigen in the context of MHC class I molecules and carry out direct cytotoxic reactions that kill infected or neoplastic cells 269 .

A unique clone-specific cell surface protein complex, the T cell receptor (TCR), specifically recognizes antigens and participates in the developmental selection of T cells that can recognize pathogens but are self-tolerant 270 . The TCR complex comprises highly polymorphic single α- and β-glycoprotein chains (a small T cell population harbours γ- and δ-chains instead) that contain variable and constant regions, akin to immunoglobulins, and a group of non-polymorphic signalling chains, called CD3 γ, δ, ε and ζ. A vast repertoire of T cell clonotypes with unique specificities is generated through rearrangement of α- and β-chain gene segments within the genome of each T cell 271 . Following clonotype production, positive and negative thymic selection functions to entrain a ‘tolerant’ immune system, one that efficiently responds to pathogens or cancer cells but generally ignores or ‘tolerates’ self-tissues as non-immunogenic 269 , 270 .

Antigen stimulation of the TCR is necessary for T cell activation and proliferation, but an additional signal, termed co-stimulation, is required for phosphorylation events crucial for early signal transduction 272 . The non-polymorphic surface protein CD28 and its family members are the most potent co-stimulatory receptors on T cells, as elegantly demonstrated by the synergism of anti-CD28 stimulatory antibodies and TCR engagement on T cell activation and proliferation 273 , 274 . Additional evidence was provided by studies demonstrating the efficient inhibition of T cell activation and proliferation by inhibitory anti-CD28 antibodies 275 , 276 , 277 , 278 . The ligands for CD28, B7-1 and B7-2, are expressed on antigen-presenting cells and are upregulated when these cells encounter microorganisms that activate Toll-like receptors or other pathogen sensors 279 , 280 . Inhibitory molecules, including cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PD1), are induced during immune responses and represent a ‘checkpoint’ to dampen T cell hyperactivation 281 (see Fig. 2 ). The polymorphic TCR signals through a complex of three sets of dimeric CD3 chains, ε–δ, γ–δ and ζ– ζ 282 . The intracellular portions of the CD3 chains contain immunoreceptor tyrosine-based activation motifs that are phosphorylated by lymphocyte-specific protein kinase (LCK), a SRC family kinase 283 . At rest, the surface signalling protein CD45 exhibits phosphatase activity that blocks LCK function 284 . Following activation, CD45 removes an inhibitory phosphate on LCK, permitting phosphorylation of ζ chain-associated protein kinase 70 (ZAP70), a SYK kinase family member that binds to immunoreceptor tyrosine-based activation motifs in the CD3 ζ-chain and recruits the linker for activation of T cells (LAT) and phospholipase Cγ1 (PLCγ) 285 . With ample co-stimulation, downstream signalling affects calcium release, the activation of the GTPase RAS and transcriptional reprogramming essential for activated T cell function 286 .

Following activation, circulating naive T cells have three major fates in the periphery (Fig. 1 ). First, the effector T cell population can contract through apoptosis as the immune response resolves (cytokine withdrawal) or following repeated high-dose stimulation (restimulation-induced cell death) 287 , 288 , 289 . T cells can also exhibit an exhausted phenotype induced by repeated low-dose and low-affinity stimulation, as seen in chronic infections and neoplastic processes 88 . Lastly, a subset of these effector cells are involved in long-term immunological memory. Memory T cells are primed to react more vigorously to the same antigen during a subsequent encounter, making them critical mediators of immune recall responses to pathogens and tumours 290 . Leveraging the power of technological advances in molecular biology, recent single-cell RNA sequencing and epigenomic studies have provided additional molecular insight into T cell fates and the corresponding features of immunotherapy-responsive T cells. These studies collectively implicate that complex transcriptomic, epigenomic and clonotypic changes of tumour-infiltrating T cells determine the success of immunotherapy 291 , 292 , 293 , 294 .

Immune checkpoint therapy

Several evolutionarily conserved negative regulators of T cell activation act as ‘checkpoint molecules’ to fine-tune the immune response and regulate hyperactivation. Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD1) are the most potent examples of T cell immune checkpoint molecules. They exert their biological effect at distinct body sites and times during the T cell lifespan 8 . Therefore, they complement each other functionally and ensure that T cell responses preserve self-tolerance while effectively protecting the body from pathogens and neoplasia. CTLA4 and PD1 have been successfully targeted by several pioneering research groups as treatments for a wide variety of recalcitrant cancers, research that ultimately earned James P. Allison and Tasuku Honjo the 2018 Nobel Prize in Physiology or Medicine.

CTLA4 biological function

After the discovery of T cell co-stimulation mediated by the surface protein CD28 (Box 1 ), the search for additional immune regulators led to the identification of CTLA4, a receptor with structural and biochemical similarities to CD28, as a new immunoglobulin superfamily member 9 , 10 . The CTLA4 and CD28 genes are found in the same region of chromosome 2 (2q33.2) and are selectively expressed in the haematopoietic compartment 11 . However, in contrast to the high levels of basal CD28 expression on conventional T cells, CTLA4 is expressed at a low basal level and is strongly induced following antigen activation. Interestingly, CD4 + CD25 + regulatory T (T reg ) cells, which have an immunosuppressive function, express CTLA4 constitutively. Structurally, both CTLA4 and CD28 form membrane-bound homodimers comprising an extracellular immunoglobulin-like domain, a transmembrane region and a cytoplasmic tail capable of recruiting signalling proteins and controlling surface expression 10 , 12 , 13 . The trafficking of CTLA4-containing vesicles to the cell surface after activation is controlled by a physical interaction with the lipopolysaccharide-responsive and beige-like anchor protein (LRBA) 13 . The sequence similarity between CTLA4 and CD28 is highest within their extracellular binding domain and they therefore bind to the same ligands, called B7-1 (also known as CD80) and B7-2 (also known as CD86), which are expressed by antigen-presenting cells (APCs; Box 1 ). However, CTLA4 has greater affinity and avidity than CD28 for B7 ligands, representing a key difference in their biology 14 , 15 , 16 .

With further characterization, it became clear that CD28 and CTLA4 had opposite immunoregulatory functions. For example, soluble CTLA4 was shown to inhibit the proliferation of T cells co-cultured with B7-expressing APCs because it interfered with the CD28–B7 interaction 14 . T cell receptor (TCR) signalling studies unequivocally demonstrated that CTLA4 inhibits T cell activation and proliferation 12 , 17 , 18 . The negative tolerogenic role of CTLA4 was also evident in vivo, because Ctla4 -knockout mice developed a characteristic T cell-mediated lymphoproliferative autoimmune disease 19 . The absence of Ctla4 was sufficient to cause this phenotype, as treatment with an engineered soluble version of a CTLA4:Fc fusion protein ( CTLA4Ig ) and genetic crosses to B7-deficient mice ameliorated disease 20 , 21 . The autoimmune lymphoproliferative disorder caused by Ctla4 loss depends on the activity of CD28 because mutation of an LCK-binding carboxy-terminal proline motif in the intracellular tail of CD28 abrogates disease in mouse models 22 . Moreover, human patients with CTLA4 haploinsufficiency exhibit similar severe multiorgan lymphocytic infiltration and autoimmunity (CHAI disease) that can be treated with abatacept, an FDA-approved CTLA4Ig 23 , 24 .

CTLA4 restrains T cell activation through multiple mechanisms: by directly antagonizing CD28, by competing for co-stimulatory ligands, by preventing immune conjugate formation and by recruiting inhibitory effectors 25 (Fig. 2 ). To directly oppose CD28 activity, intracellular vesicles release CTLA4 at the immunological synapse where it associates with the TCR 26 . In the context of the immunological synapse, CTLA4 can also reorganize the cytoskeleton and disturb T cell–APC immune conjugate formation 27 . CTLA4 also mediates the internalization of its ligands, thereby preventing their binding to CD28, which, in turn, reduces IL-2 secretion and T cell proliferation 17 , 28 , 29 . Lastly, phosphatases, including SH2 domain-containing tyrosine phosphatase 2 (SHP2) and protein phosphatase 2A (PP2A), are recruited and interact with the cytoplasmic tail of CTLA4, thereby contributing to its negative effect on T cell activation. SHP2 is an inhibitor of phosphorylation of the CD3 ζ-subunit of the TCR and also inhibits phosphorylation of the adaptor protein linker of activated T cells (LAT) 30 , 31 . PP2A is hypothesized to inhibit extracellular signal-regulated kinase (ERK), a kinase that acts as a signalling protein downstream of the TCR 32 . However, there is significant debate about which of the molecules that associate with the cytoplasmic tail of CTLA4 are most important for inhibiting T cell activity. Nevertheless, these inhibitory signals reduce the activation of transcription factors, such as activator protein 1 (AP-1), nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT), which reprogrammes T cells towards an anergic fate 29 , 33 .

Before activation, antigen-presenting cells (APCs) load antigen onto MHC molecules to prepare for contact with a T cell that displays a cognate T cell receptor (TCR) while also providing necessary co-stimulatory ligands B7-1 and B7-2. The inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA4) is contained within intracellular vesicles in naive T cells, whereas it is constitutively expressed on the cell surface of CD4 + CD25 + regulatory T (T reg ) cells. Both classes of T cells express the co-stimulatory receptor CD28. Early after activation, generally in the lymphoid tissue, T cells are activated when their TCRs bind to their cognate antigen presented by APCs in conjunction with CD28 binding to B7-1/B7-2. Also, the activated T cells begin the process of displaying CTLA4 on the cell surface. T cells within peripheral tissues upregulate PD1 at the mRNA level early after activation. Late after activation, in lymphoid tissue, CTLA4 expressed by activated T cells binds to the B7-1 and B7-2 molecules on APCs, thereby preventing their binding to CD28 and promoting anergy by decreasing the T cell activation state. At the same time, constitutive expression of CTLA4 on T reg cells leads to trans-endocytosis of B7 ligands and interferes with the CD28 co-stimulatory ability of APCs. Late after activation in peripheral tissues, PD1 is further upregulated transcriptionally, leading to greater surface expression of programmed cell death 1 (PD1), which binds to its ligands PDL1 and PDL2, thereby promoting T cell exhaustion at sites of infection or when confronted with neoplasms. Image courtesy of the National Institute of Allergy and Infectious Diseases.

Beyond its function in activated conventional T cells, CTLA4 expression on T reg cells is essential for the direct and indirect immunosuppressive activity of these cells 34 , 35 . In vitro studies showed that CTLA4 was necessary for anti-inflammatory cytokine release by T reg cells, which reduces polyclonal activation and proliferation of conventional T cells nearby 36 , 37 . This result was confirmed in vivo by adoptive transfer of CTLA4-bearing T reg cells to prevent autoimmunity induced by CTLA4-deficient T cells that had been transferred to T cell- and B cell-deficient mice ( Rag –/– mice) 38 , 39 . This treatment effect was nullified by antibody-mediated neutralization of CTLA4 (refs 38 , 40 , 41 ). Thus, T reg cell-expressed CTLA4 can compensate for lack of CTLA4 expression by conventional T cells 42 , 43 . Beyond direct immunosuppression, T reg cells also prime dendritic cells to induce anergy of conventional T cells in a CTLA4-dependent fashion by binding to B7 ligands on APCs, followed by internalizing and degrading them, a process termed trans-endocytosis 28 , 44 .

CTLA4 blockade in cancer

The recognition of CTLA4 as a negative regulator of T cell activation gave rise to the idea that blocking its actions could unleash a therapeutic response of T cells against cancer 45 (Fig. 3 ). James Allison and colleagues first tested this idea and demonstrated that neutralizing anti-CTLA4 antibodies enhanced antitumoural immunity in mice against transplanted and established colon carcinoma and fibrosarcoma 46 . In addition, during rechallenge, animals treated with anti-CTLA4 were able to rapidly eliminate tumour cells through immune mechanisms, providing evidence that blocking of CTLA4 induces long-lasting immunological memory 46 , 47 . Although CTLA4-targeted monotherapy was shown to confer benefit in animal models of brain 48 , ovarian 49 , bladder 50 , colon 46 , prostate 47 and soft tissue 46 cancers, less immunogenic cancers, including SM1 mammary carcinoma 51 and B16 melanoma 52 , did not respond as favourably. Furthermore, heterogeneity between cancer models yielded discordant tissue-specific results 45 , 53 . In addition, a greater tumour burden correlated with reduced tumour responses to anti-CTLA4 treatment because larger tumours foster a more robust anti-inflammatory tumour microenvironment 45 , 49 .

Cytotoxic T lymphocyte antigen 4 (CTLA4)-blocking antibodies (α-CTLA4), especially when bound to an Fc receptor (FcR) on an antigen-presenting cell (APC), can promote antibody-dependent cellular cytotoxicity (ADCC). CD4 + CD25 + regulatory T (T reg ) cells express higher amounts of CTLA4 than conventional T cells and are therefore more prone to α-CTLA4-induced ADCC than conventional T cells. In addition, α-CTLA4 can bind to CTLA4 on the surface of the T reg cell and prevent it from counter-regulating the CD28-mediated co-stimulatory pathways that are playing a role in T cell activation. At the same time, α-CTLA4 can also promote T cell responses by blocking CTLA4 on the surface of conventional T cells as they undergo activation. TCR, T cell receptor. Adapted from ©2019 Fritz, J. M. & Lenardo, M. J. Originally published in J. Exp. Med . https://doi.org/10.1084/jem.20182395 (ref. 135 ).

Despite the mixed success in preclinical studies, mAbs targeting CTLA4 proved effective in clinical trials of melanoma 45 . Ipilimumab, a human IgG1κ anti-CTLA4 mAb, gained FDA approval in 2011 for non-resectable stage III/IV melanoma following evidence that it elicited potent tumour necrosis 54 and conferred a 3.6-month short-term survival benefit 55 . Long-term survival data demonstrated that 22% of patients with advanced melanoma treated with ipilimumab benefited from an additional 3 years or more of life 56 . Additional long-term studies have demonstrated the durability of this survival benefit, indicating the persistence of antitumoural immunity following CTLA4 blockade 56 , 57 . Unfortunately, trial results in renal cell carcinoma 58 , non-small-cell lung cancer 59 , small-cell lung cancer 60 and prostate cancer 61 have yielded less impressive effects than those seen in patients with melanoma. Tremelimumab, an IgG2 isotype form of a CTLA4-blocking antibody, has yet to receive FDA approval as it did not increase survival in advanced melanoma 62 . It is hypothesized that effectiveness varies between ipilimumab and tremelimumab owing to differences in binding kinetics and the capacity to mediate antibody-dependent cell-mediated cytotoxicity 63 , 64 .

The mechanisms of CTLA4-mediated tumour regression are pleiotropic but unified by the action of one cell type, the T lymphocyte (Fig. 3 ). T cell responses are necessary for the therapeutic effects of CTLA4-targeted agents because T cell depletion in animal models abolishes tumoricidal activity 65 . Inhibition of CTLA4 enhances T cell clonal responses to tumour-associated neoantigens and a high neoantigen burden portends a favourable response to anti-CTLA4 therapy 66 , 67 . Apart from boosting effector T cell responses, anti-CTLA4 therapy depletes local intratumoural T reg cells through antibody-dependent cell-mediated cytotoxicity in mouse models and shifts the balance of the tumour microenvironment away from immunosuppression 68 , 69 . This phenomenon requires further study in human cancer as current data are inconclusive 70 , 71 . The relative role of effector T cells and T reg cells in conferring a clinical benefit has been contested, although specific blocking of CTLA4 in both cell populations can lead to synergistic increases in tumour regression 69 . Overall, current data suggest that the most critical factor in predicting outcome is the ratio of effector T cells to T reg cells infiltrating the tumour 45 , 49 .

PD1/PDL1 biological function

PD1 was first identified in 1992 as a putative mediator of apoptosis, although later evidence suggested a role in restraining immune system hyperactivation, analogous to CTLA4 (ref. 72 ). As a type 1 transmembrane glycoprotein within the immunoglobulin superfamily, PD1 exhibits a 20% and 15% amino acid identity to CTLA4 and CD28, respectively 73 . Human PD1 is expressed on T cells after TCR stimulation and binds the B7 homologues PDL1 (also known as B7-H1) and PDL2 (also known as B7-DC), which are present constitutively on APCs and can be induced in non-haematopoietic tissues by pro-inflammatory cytokines 74 , 75 , 76 . In this review, we refer to PD1 and its ligands as the ‘PD1 axis’. The predominant role of the PD1 axis in the negative regulation of T cell activation became clear in 1999 when loss of the mouse PD1 orthologue, Pdcd1 , was found to cause autoimmunity in vivo. C57BL/6 mice lacking functional PD1 protein developed splenomegaly 77 . Ageing of these animals led to mild T cell-mediated lupus-like glomerulonephritis and arthritis that was exacerbated by concurrent lpr mutations in the Fas gene 78 . Characterization of additional mouse strains showed that Pdcd1 –/– mice of the BALB/c strain exhibited cardiac inflammation leading to dilated cardiomyopathy 79 . By comparison, non-obese diabetic Pdcd1 –/– mice had accelerated type 1 diabetes mellitus compared with their Pdcd1 -sufficient counterparts 80 . The heterogeneous and late-onset autoimmune phenotypes of Pdcd1 –/– mice were distinct from Ctla4 –/– animals, demonstrating that the PD1 axis regulates T cell biology differently to CTLA4. Spatially, CTLA4 exerts its regulatory effect predominantly within lymphoid organs, whereas PD1 tends towards tempering T cell activation locally within peripheral tissues 8 . Temporally, PD1 acts later in the course of T cell activation and fate determination. Overall, the PD1 axis plays a unique role in maintaining T cell tolerance to self.

PD1 restrains immune responses primarily through inhibitory intracellular signalling in effector T cells and T reg cells 81 . The immunoreceptor tyrosine-based switch motif and the immunoreceptor tyrosine-based inhibitory motif of PD1 are phosphorylated and recruit the phosphatases SHP1 and SHP2, which dephosphorylate, and thereby inactivate, downstream effectors (that is, the CD3 ζ-subunit and ZAP70) that are important for early T cell activation 76 and CD28 signalling 82 . Both CTLA4 and PD1 inhibit protein kinase B (PKB; also known as AKT) signalling to reduce glucose uptake and utilization, the former through PP2A and the latter by reducing phosphoinositide 3-kinase (PI3K) activity 83 . In contrast to CTLA4, the PD1 axis is essential for controlling the continued activation and proliferation of differentiated effectors; when PD1 engages its ligands, it can induce a state of T cell dysfunction called T cell exhaustion 84 , 85 , 86 . However, what determines whether PD1 mediates exhaustion or apoptosis in certain contexts is still an active area of research. One model suggests that the interaction between PI3K signalling and the mitochondrial B cell lymphoma-extra large (BCL-X L ) protein is a critical control point at which PD1-mediated P13K inhibition reduces BCL-X L and promotes apoptosis 25 , 83 . Beyond regulating conventional T cells, PDL1 on APCs can control T reg cell differentiation and suppressive activity 87 . Unfortunately, tumour cells can exploit this mechanism by upregulating PD1 ligands to induce T cell exhaustion and generate a tumour microenvironment that facilitates tumour growth and invasion 88 .

PD1/PDL1 blockade in cancer

Once the PD1 axis was implicated in the negative regulation of T cells, preclinical work examined whether inhibitors of this pathway could be used for cancer treatment and biomarker discovery. First, overexpression of PDL1 or PDL2 in cancer cell lines was found to constrain the CD8 + T cell cytotoxic antitumour response, whereas tumours were rejected in mice without functional PD1 (refs 89 , 90 ). Second, blockade of PD1 suppressed the growth of transplanted myeloma cells in syngeneic animals 90 . Conversely, transplanted cells overexpressing PDL1 or PDL2 in syngeneic mice allowed for increased tumour colonization, burden and invasiveness 90 . Neutralizing the PD1 axis using mAbs 89 , 91 or secreted PD1 extracellular domains 92 reversed these effects and enhanced T cell cytotoxicity towards tumour cells 90 (Fig. 4 ). Rescuing CD8 + T cell cytotoxicity by PD1 blockade depends on the expression of CD28 as PD1-mediated immunomodulation is lost in the context of CTLA4Ig, B7 blockade or CD28 conditional-knockout mice 92 . In addition, reinvigorated T cells in the peripheral blood of patients with lung cancer following PD1 blockade were shown to express CD28 (ref. 93 ). PD1 inhibition not only augments antitumoural immunity but also limits haematogenous seeding of B16 melanoma and CT26 colon carcinoma metastases in mouse models 94 . Thus, PD1/PDL1 blockade can both enhance tumour cytolysis and limit metastasis. Apart from a role of PD1 and its ligands in cancer treatment, multiple studies have also shown a negative correlation between human tumour expression of proteins involved in the PD1 axis and prognosis, indicating the utility of these proteins as potential biomarkers 95 , 96 , 97 .

Activated T cells express programmed cell death 1 (PD1), which engages with its specific ligand (PDL1 or PDL2) to dampen activation. Blocking of the PD1 axis through the administration of an anti-PD1 (or anti-PDL1 or anti-PDL2) antibody prevents this inhibitory interaction and unleashes antitumoural T lymphocyte activity by promoting increased T cell activation and proliferation, by enhancing their effector functions and by supporting the formation of memory cells. Consequently, more T cells bind to tumour antigens presented on tumour cells by MHC molecules via their T cell receptors (TCRs). This ultimately leads to the release of cytolytic mediators, such as perforin and granzyme, causing enhanced tumour killing. APC, antigen-presenting cell. Adapted from ©2019 Fritz, J. M. & Lenardo, M. J. Originally published in J. Exp. Med . https://doi.org/10.1084/jem.20182395 (ref. 135 ).

Following preclinical success, mAbs designed to counteract negative immunoregulation by the PD1 axis were developed and efficacy was shown in clinical trials 98 . Development was initiated by Medarex (ultimately purchased by Bristol-Myers Squibb) in 2001 (ref. 99 ). In 2010, a phase I trial demonstrated that PD1 blockade was well tolerated and could promote antitumoural responses 100 . In 2014, the humanized and fully human anti-PD1 mAbs pembrolizumab and nivolumab (both IgG4) became the first FDA-approved PD1-targeted therapeutics for refractory and unresectable melanoma 101 , 102 , 103 , 104 . In a head-to-head comparison, pembrolizumab showed better 6-month progression-free survival than ipilimumab and conferred an overall survival benefit 105 , 106 . Clinical trials of nivolumab demonstrated an overall survival of 72.9% at 1 year compared with 42.1% survival in the group of patients treated with the chemotherapeutic dacarbazine 104 . In 2015, pembrolizumab was approved for the treatment of PDL1-expressing non-small-cell lung carcinoma because it provided a 4.3-month increase in progression-free survival compared with platinum-based chemotherapeutics and was more effective than the chemotherapeutic paclitaxel 107 , 108 . Increased PDL1 expression on the target tumour was associated with improved responses to PD1 axis blockade 109 . Additional successful clinical trials expanded the use of pembrolizumab to head and neck squamous cell carcinoma 110 , Hodgkin lymphoma 111 , urothelial carcinoma 112 , gastric/gastro-oesophageal junction cancer 113 and tissue-agnostic carcinoma with a high degree of microsatellite instability 114 . Following approval in tissue-agnostic cancers with microsatellite instability, pembrolizumab became the first drug to be approved based on a molecular biomarker rather than by cancer site. However, the immunosuppressive microenvironment of different tissues makes it hard to predict which patients will benefit 115 , 116 . Similar to prembrolizumab, the use of nivolumab has since been extended to renal cell carcinoma 117 , head and neck squamous cell carcinoma 118 , urothelial carcinoma 119 , hepatocellular carcinoma 120 , Hodgkin lymphoma 121 and colorectal cancer with a high degree of microsatellite instability 122 . As was seen with anti-CTLA4 therapy, long-term survival analyses demonstrate a long-lasting immune-mediated survival benefit following PD1 blockade 123 . However, the reason why PD1 blockade has demonstrated broader clinical utility than anti-CTLA4 treatment has remained elusive. It is hypothesized that the difference may be because the PD1 axis is frequently co-opted by tumours via ligand expression, whereas CTLA4 represents a broader immunoregulatory circuit 74 , 124 .

PDL1 is also targetable by specific antibodies that have proven effective treatments in multiple forms of cancer. In 2016, the first PDL1-targeted humanized mAb, atezolizumab (an IgG4 antibody), was approved for treatment of urothelial carcinoma. An overall response rate of 15% was deemed statistically significant based on historical control data, although responses were dependent on tumour PDL1 expression status 125 . Unfortunately, additional trial data have not demonstrated that atezolizumab has clinical efficacy beyond the standard of care in urothelial carcinoma, although it is less toxic than traditional chemotherapy 126 . Indications have since expanded to include the treatment of non-small-cell lung carcinoma 127 , triple-negative breast cancer 128 and small-cell lung cancer 129 . Additional anti-PDL1 human mAbs, avelumab and durvalumab, entered the market in 2017 (ref. 98 ). Avelumab is used for the treatment of Merkel cell carcinoma 130 , urothelial carcinoma 131 and advanced renal cell carcinoma 132 . Duvalumab is used for urothelial carcinoma 133 and non-small-cell lung cancer 134 . Therefore, similar to PD1, blockade of PDL1 has been effective in difficult-to-treat forms of cancer.

Adverse effects of checkpoint blockade

Blocking a naturally occurring central immune checkpoint unleashes powerful immune effector mechanisms that may not respect the normal boundaries of immune tolerance to self-tissues 135 . Ctla4- and Pdcd1 -knockout mice provided a glimpse into the spectrum of autoimmune responses that occur in humans during immune checkpoint blockade therapy 19 , 77 , 78 , 79 . Human loss-of-function mutations in CTLA4 and its interacting regulatory protein, LRBA , also mirror the immune-related side effects observed with anti-CTLA4 therapy 13 , 24 . On the basis of a meta-analysis of trial data sets, immune-related adverse events are estimated to occur in 15–90% of patients 55 . More severe events requiring intervention are observed in 30% and 15% of patients treated with CTLA4 and PD1 axis inhibitors, respectively 136 . The common immune feature of toxicity is the loss of naive T cells and the accumulation of overactive memory T cells that invade peripheral organs, such as the gastrointestinal tract and lungs, and cause inflammatory damage. Keratinized and non-keratinized mucosa appear to be the most susceptible, as approximately 68% and 40% of treated patients exhibit pruritis and mucositis, respectively 137 , 138 . Anti-CTLA4 therapy carries an increased risk of severe autoimmune complications compared with therapies targeting the PD1 axis, as was observed in knockout mice and in clinical studies 19 , 77 , 78 , 79 , 80 , 139 . In addition, data from dose-escalation trials support the claim that anti-CTLA4 agents elicit dose-dependent responses not seen with therapies targeted at the PD1 axis 107 , 139 . Toxicities affecting the gastrointestinal tract and brain are more common with anti-CTLA4 therapy, whereas patients treated with PD1 axis-targeted therapies are at higher risk of hypothyroidism, hepatoxicity and pneumonitis 137 . However, as the number of indications treated with checkpoint blockade increases and more patients are treated, rarer side effects in a wider spectrum of organs and heterogeneous responses have manifested 137 . For example, hyperprogression of disease has been observed in a minority of patients with various tumour types treated with PD1 inhibitors 140 , 141 , 142 . Most recently, it was shown that the PD1 inhibitor nivolumab can lead to the rapid progression of disease in patients with adult T cell leukaemia/lymphoma, providing evidence for a role of tumour-resident T reg cells in the pathogenesis of this lymphoma 143 . Multiple immune-related response criteria have been developed to better categorize patient responses to checkpoint blockade. In addition, these criteria aim to distinguish progression from pseudoprogression, a phenomenon in which patients treated with CTLA4 or PD1 inhibitors experience a period of progression followed by rapid tumour clearance 144 , 145 . Overall, checkpoint blockade leads to autoimmune toxicities with a therapy-specific pattern of organ involvement, as predicted by the phenotypes of animals genetically deficient for checkpoint molecules.

Interestingly, preclinical immune checkpoint therapy studies did not demonstrate major adverse effects in vivo and, thus, were not great predictors of human toxicities 146 . This is thought to be due to the short time frame of these studies and the inbred nature of mouse strains 146 . Recently developed humanized mouse models represent a platform that better recapitulates side effects due to checkpoint therapy 146 , 147 . Nevertheless, toxicity associated with immune checkpoint blockade is tolerated better than the toxicities associated with traditional chemotherapeutics, making these therapies attractive for quality of life reasons beyond their survival benefit 98 , 148 .

Recent research has aimed to improve the side-effect profiles and clinical response of immune checkpoint blockade through the modification of existing antibodies and the engineering of novel delivery methods. It was recently shown that abnormal CTLA4 recycling and subsequent lysosomal degradation was a mechanism that contributes to toxicities and reduced drug effectiveness. Modified pH-sensitive antibodies that do not interfere with LRBA-mediated CTLA4 recycling were shown to limit adverse events and improve clinical outcomes in established tumours in mouse models, which may ultimately broaden clinical utility 149 , 150 . Additional research has focused on developing biomaterials for the localized administration of checkpoint inhibitors 151 . For example, compared with systemic delivery, transdermal patch delivery of anti-PD1 antibodies was better tolerated and unleashed a more robust antitumoural response in a mouse model of melanoma 151 . A broad field of research is currently aimed at discovering novel methods to reduce toxicities associated with checkpoint therapy and to increase clinical benefit in a greater variety of tumours.

Clinical management of drug-related toxicities is the same for all checkpoint drugs, and toxicities are graded according to the 2009 National Cancer Institute Common Terminology Criteria for Adverse Events severity scale 137 , 152 . Mild (grade 1) toxicities are not typically treated. In the setting of grade 2 or 3 adverse events, checkpoint inhibitors are discontinued until symptoms and laboratory-value abnormalities resolve. Glucocorticoids are also used to effectively control immune hyperactivity. Infliximab and other immunosuppressive agents can be used when glucocorticoids fail. Life-threatening (grade 4) toxicities necessitate the complete discontinuation of therapy and the use of life-saving measures, as required. Active monitoring of symptoms and laboratory parameters is recommended in order to prevent death due to checkpoint blockade (grade 5).

Current research is aimed at identifying predictive biomarkers for organ-specific toxicities due to checkpoint therapy. For example, neutrophil activation, as measured by increased expression of the biliary glycoprotein CEACAM1 and the cell surface glycoprotein CD177, correlates with gastrointestinal-related side effects in patients treated with ipilimumab 153 . Increases in eosinophil counts and release of the pro-inflammatory cytokine IL-17 are associated with toxicity regardless of the organ affected 154 , 155 . Pharmacogenomic profiling (using genetic information to predict responses to drugs) may provide more insight into the relevant genes and pathways mediating toxicity 137 . Ultimately, the hope is that genetic, biochemical or metabolic profiling could either pre-screen or rapidly detect individuals likely to experience the most severe adverse reactions to checkpoint therapy.

Adoptive T cell transfer therapy

Adoptive T cell (ATC) therapy, in which autologous or allogenic T cells are infused into patients with cancer, has shown considerable promise in recent years. The viability of this type of therapy was first shown by Southam et al. in 1966, when half of the patients with advanced cancer demonstrated tumour regression following co-transplantation with patient-derived leukocytes and autologous tumour cells 156 . Allogenic haematopoietic stem cell transplants for leukaemia represented the first effective adoptive transfer approach deployed clinically, and clinical improvement was shown to be mediated by a T cell graft versus tumour response 157 .

ATC with tumour-infiltrating lymphocytes

ATC therapy using tumour-infiltrating lymphocytes (TILs) for the treatment of metastatic melanoma was pioneered at the National Cancer Institute in the late 1980s 158 . Lymphocytes isolated from a cancer biopsy were greatly expanded with IL-2 and then reinfused intravenously into the same patient with a large bolus of IL-2. The objective response rate was 34%; however, the median duration of response was only 4 months and few patients experienced a complete response 159 . Later studies incorporating lymphodepletion before ATC therapy in 93 patients with metastatic melanoma were more successful, with complete tumour regression in 20 (22%) patients, 19 of whom were still in complete remission 3 years after treatment 160 . The screening and enriching for neoantigen-specific TILs, made possible by high-throughput technologies, recently demonstrated promise in a patient with metastatic breast cancer 161 . In addition, knockdown of the gene encoding cytokine-inducible SH2-containing protein ( Cish ), a negative regulator of TCR signalling, was shown to boost the antitumoural response of ATC therapy in mouse models 162 . However, in order for TIL-based ATC therapy to elicit durable responses (Fig. 5 ), effector T cells with antitumour activity must be present in the tumour, which is not the case for many cancer types 163 . Other innovative approaches to tweak T cell activity and proliferation may allow for a greater palette of treatments to be developed.

a | Tumour-infiltrating lymphocytes (TILs) are isolated from a patient tumour biopsy and expanded ex vivo with IL-2. TILs are then infused into a patient who has undergone lymphodepletion to provide a niche for the transferred TILs to expand, act as effector cells and generate immunological memory. As the T cells were derived from the tumour, it is assumed that a good proportion can recognize tumour-associated antigens (TAAs) or neoantigens. b | The physiological T cell receptor (TCR) complex gains its specificity from polymorphic α- and β-glycoprotein chains that have an antigen-binding portion and a conserved domain that associate with and signal through a group of non-polymorphic proteins, CD3 γ, δ, ε and ζ. Bioengineering of the TCR α- and β-glycoprotein antigen-binding domain (purple), while preserving the conserved domains (Cα and Cβ), allows for the development and expansion of T lymphocytes with specificity to tumour neoantigens. c | Originally, chimeric antigen receptors (CARs) were composed of an extracellular single-chain fragment of an antibody variable region coupled to a CD3 ζ-signalling domain. Poor expansion and functionality of these first-generation CARs led to the development of second and third-generation CARs containing intracellular modules from co-stimulatory molecules (CD28 and/or 4-1BB) that provide additional signals necessary to fully activate the T cell. Subsequent generations of CAR T cells contain further modifications to improve antitumour efficacy. For example, fourth-generation ‘armoured’ CAR T cells have been engineered to secrete pro-inflammatory cytokines, such as IL-12, to overcome immunosuppression in the tumour microenvironment. The chimeric cytokine receptor 4αβ, comprising the ectodomain of IL-4Rα fused to the IL-2/IL-15Rβ chain, signals in response to IL-4, an abundant cytokine in numerous tumour types. V H , variable heavy chain; V L , variable light chain.

Engineered lymphocytes for ATC

The challenges associated with expanding tumour-specific T cells in vitro led to the development of TCR-engineered lymphocytes (Fig. 5 ). However, these cells are limited to responding to tumour antigens presented by the MHC (also known as human leukocyte antigen (HLA) in humans) rather than surface antigens on tumour cells 163 . However, synthetic chimeric antigen receptors (CARs) can bypass MHC restriction and direct specific cytotoxicity to a target molecule on the surface of the malignant cell. Isolated T cells from the patient (or allogeneic donor) are genetically modified to express CARs and then expanded and infused into the patient. This overcomes the problem that tumour cells often downregulate MHC molecules, which leaves the cell unable to present antigen to conventional T cells 164 . CARs comprise an antigen-binding domain, most often from the variable regions of antibodies, linked to signalling domains of the TCR and various co-stimulatory molecules (Fig. 5 ). Given the domain modularity of cell surface signalling proteins, mixes and matches of extracellular targeting domains and internal signal transduction domains can be assembled using protein engineering. This offers many options to tailor CARs to specific tumours. The first generation of CAR T cells relied only on the CD3 ζ-chain to simulate TCR signalling 165 , but this design was ineffective in clinical trials owing to limited T cell proliferation and cytokine production 166 , 167 . Subsequent generations of CAR T cells have been engineered to include domains from CD28, CD40 ligand and other positive regulators of T cell activation to potentiate activation and cytotoxicity in vivo 168 , 169 , 170 , 171 . An engineered single-chain PD1 blocker has also demonstrated similar enhanced efficacy to second-generation CAR T cells with solely a CD28 domain 172 . Even though CAR T cells are typically engineered using retroviral transduction, recent work has used CRISPR–Cas9 technology. CRISPR–Cas9 can be used to edit the TCR germline sequence directly, which could lead to more uniform CAR T cell generation and, ultimately, better efficacy 173 .

A limitation to the development of CAR T cell therapies is the requirement for a distinct tissue-restricted target antigen on the tumour cell surface. For example, CAR T cells designed with specificity for the cell surface molecule CD19, which is expressed by all B cells, have been successful in the treatment of B cell malignancies. The first clinical deployment of second-generation CD19-specific CAR T cells led to durable responses in chronic lymphocytic leukaemia 174 . Additional clinical trials of CD19-specific second-generation CAR T cells in B cell acute lymphoblastic leukaemia (B-ALL) led to remission in all patients with B-ALL who were tested 175 . A follow-up report on patients with B-ALL enrolled in this clinical trial showed complete remission of disease in 44 of 53 (83%) patients with a median follow-up of 29 months 176 . Similar successes were reported for patients with diffuse large B cell lymphoma 177 , leading to FDA approval for these B cell malignancies in 2017.

The clinical success of CAR T cell therapy for the treatment of B-ALL and diffuse large B cell lymphoma is due, in part, to targeting the CD19 antigen, an ideal candidate owing to its high expression in certain B cell malignancies and specificity to the B cell lineage. Crossover targeting of normal CD19 + B cells does not hamper therapy or cause severe side effects. However, even as an ideal target, CD19 antigen loss is a common cause of treatment failure. CD22 is another antigen commonly expressed by malignant cells in B-ALL and has shown promise as a target for CAR T cell therapy in a phase I trial 178 . Other targets, especially tumour neoantigens, are currently being investigated for haematological malignancies that do not express CD19, as well as for solid tumours 179 , 180 . B cell maturation antigen (BCMA)-targeted CAR T cell therapy is poised for FDA approval for multiple myeloma in 2020 on the basis of promising preclinical and clinical data 181 , 182 . However, owing to reported patient relapses, the investigation of additional target antigens continues. A preclinical study recently identified another target antigen, GPRC5D, with comparable efficacy and toxicity to BCMA-targeted CAR T cell therapy 183 . Thus far, CAR T cell therapy has only been modestly successful for solid tumours 184 , 185 , 186 and innovative approaches to improve therapy are underway 179 . A recently identified pan-cancer target, B7-H3 (also known as CD276), has demonstrated success in multiple paediatric solid tumour models 187 . In addition to directly acting as cytolytic agents, CAR T cells can also target the unhospitable tumour microenvironment and revive exhausted T cells 188 , 189 . For example, a new generation of ‘armoured’ CAR T cells engineered to produce IL-12 can overcome immunosuppression by T reg cells and myeloid cells in the tumour environment, promote CD8 + T cell cytolytic activity 190 and enhance myeloid cell recruitment and antigen presentation 191 , 192 . Preclinical models using IL-12-expressing CAR T cells that target the conserved extracellular domain of mucin 16 (MUC16 ecto ) have shown promising results in models of ovarian cancer, a tumour with poor prognosis in advanced stages 193 , 194 . A phase I clinical trial is currently in progress for patients with ovarian, fallopian or primary peritoneal cancer 195 . The efficacy of CAR T cells may also be strengthened through co-expression of a chimeric cytokine receptor (4αβ) that stimulates proliferation in response to IL-4, a cytokine that is usually abundant in the tumour microenvironment. Preliminary studies have shown that this approach works for CAR T cells directed against different tumour-associated antigens (TAAs) 196 and clinical trials are underway in head and neck cancer 197 . In addition, overexpression of the transcription factor JUN was shown to confer resistance to CAR T cell exhaustion 198 . Overall, CAR T cells have been successful for the treatment of B cell malignancies and it will be exciting to continue research on this new treatment modality for intractable types of cancer.

Limitations and adverse effects of ATCs

Toxicities can arise from CAR T cell therapy and affect many different organ systems with a range of severity 199 . Patients most commonly experience cytokine release syndrome (CRS) and neurotoxicity 200 . CRS results from the powerful activation and proliferation of CAR T cells in vivo and typically appears quickly after cell transfer. The symptoms are often mild and flu-like but can also be severe and life-threatening, involving hypotension, high fever, capillary leakage, coagulopathy and multisystem organ failure. Serious neurological events can also occur, such as CAR T cell-related encephalopathy syndrome, typically characterized by confusion and delirium, but sometimes also associated with seizures and cerebral oedema 199 . Glucocorticoids are the first-line treatment for milder forms of CRS and CAR T cell-related encephalopathy syndrome. Tocilizumab, a humanized anti-IL-6 antibody, is a highly effective second-line treatment for CRS caused by CAR T cell therapy 201 . Other side effects of CD19-specific CAR T cell therapy include lymphopenia and hypogammaglobulinaemia 202 , which can be effectively managed with intravenous immunoglobulin therapy, similar to the treatment that patients with primary B cell immunodeficiencies receive 203 . The mechanisms behind these side effects are unclear and further research may yield ways to avoid or minimize toxicity. Recent development of a novel murine model of CRS demonstrated that it is not mediated by CAR T cell-derived IL-6 but rather by recipient macrophages that secrete IL-6, IL-1 and nitric oxide. Therefore, IL-1 blockade represents a possible novel intervention in the armamentarium against CRS 204 . Moreover, a clinical study of low-affinity CD19-specific CAR T cells demonstrated reduced toxicity and enhanced efficacy 205 . Additional efforts to reduce toxicity involve the engineering of CAR T cells with multiple receptor specificities 206 and reducing the half-life of cellular toxicity by using mRNA-based methods that allow for transient receptor expression 207 or including suicide cassettes that can be activated by exogenous agents to clonally delete the infused cells 208 .

The ATC approach necessitates a patient-specific therapy design, its cost can be prohibitive, patient access to the treatment is limited and manufacturing is challenging. In the United States, the CAR T cell therapies tisagenlecleucel and axicabtagene ciloleucel have a direct cost of US$475,000 and US$373,000 per patient, respectively 209 . However, these values do not take into account the additional costs associated with treating the severe adverse effects common to CAR T cell therapy, which are estimated to increase drug-associated costs by US$30,000 or more 209 . In comparison with CAR T cell therapy, checkpoint blockade has a price tag of approximately US$12,500 per month 210 . Patient access to CAR T cell therapies also represents a major problem as there are only a few laboratories certified to generate CAR T cells and only a few specialized tertiary care centres able to administer this therapy 211 . Lastly, variability in the manufacturing of CAR T cells and a lack of standard practices can contribute to heterogeneous outcomes 211 .

Cancer vaccines

Cancer vaccines prompt the immune system to protect the body from cancer and fall into two categories, prophylactic and therapeutic. Prophylactic vaccines against hepatitis B and human papillomavirus have been instrumental in reducing the incidence of hepatocellular carcinoma and cervical cancer, respectively 212 . These are classic vaccines used to prevent infection by oncogenic viruses. By contrast, therapeutic vaccines aim to harness the immune system to eliminate disease-causing cells that are already neoplastic 212 . An early example of this is the use of the bacillus Calmette–Guérin vaccine, comprising attenuated Mycobacterium bovis , which is generally used as a prophylactic tuberculosis vaccine but has also been repurposed as a primitive therapeutic vaccine for bladder cancer 213 .

Historically, the discovery of TAAs 214 , which are highly expressed on tumour cells and to a lesser extent on normal tissues, opened the door for further therapeutic vaccine-based approaches. However, as TAAs are often recognized by the immune system as ‘self’, viral antigens and neoantigens that are unique to a malignancy may be more suited as vaccine targets.

Early vaccination approaches in the 1970s were based on autologous tumour vaccines and involved the administration of patient-derived tumour cells together with an adjuvant or virus in order to activate polyclonal immune responses to TAAs 215 . For example, autologous tumour cells infected with Newcastle disease virus have been used in one type of cancer vaccine that has demonstrated success in preclinical models of metastatic lymphoma and melanoma 216 , 217 . Modified Newcastle disease virus-based vaccines have been engineered to express granulocyte–macrophage colony-stimulating factor (GM-CSF) in attempts to enhance efficacy 218 . Synergism of vaccine approaches with checkpoint blockade agents has also been demonstrated in some preclinical studies of melanoma 46 , 219 . Numerous autologous tumour vaccines are being investigated in phase II and phase III trials but have yet to receive FDA approval. This approach suffers from multiple limitations, most notably the difficulty in obtaining patient-derived tumour cells in certain cancer types 212 . Newer approaches include the development of personalized recombinant cancer vaccines informed by next-generation sequencing of genomic DNA from tumours.

Development of personalized recombinant cancer vaccines

Vaccines that elicit responses to tumour-derived neoantigens should induce more robust immune responses and cause fewer autoimmune-related toxicities than vaccines based on self-derived TAAs, as the T cells that are activated by such a vaccine would not have undergone negative selection during development. These factors, as well as the ability to identify neoantigens through next-generation sequencing of genomic DNA from tumours, has shifted the focus to investigating the clinical feasibility of making personalized recombinant vaccines that target neoantigens. However, although a higher mutational burden in the tumour has been shown to correlate with greater immunogenicity and survival after checkpoint blockade 66 , 220 , only a small percentage of neoantigens spontaneously generate immune responses in patients with cancer 221 . Sahin and colleagues showed that neoantigens identified through next-generation sequencing can generate antitumour responses in vivo; in mice that were vaccinated with 50 different neoantigens, 16 were immunogenic 222 , 223 . Interestingly, most neoantigens induced cytokine responses from CD4 + T cells rather than CD8 + T cells, suggesting that neoantigens are selected for MHC class II binding 222 , 223 . Other preclinical studies demonstrated effective CD4 + and CD8 + T cell responses to neoantigen vaccines in various cancer types 223 , 224 , 225 , 226 , 227 . However, recent preclinical work has also highlighted the non-overlapping role of neoantigen responses mediated by CD4 + and CD8 + T cells 228 .

To design and manufacture a personalized vaccine for clinical use, computer-based algorithms are used to identify which tumour-derived peptides could potentially form a suitable TAA or tumour neoantigen with the patient’s MHC alleles (Fig. 6 ). There are several different strategies to formulate neoantigen-based vaccines, including as synthetic peptides, mRNA, viral and DNA plasmids or antigen-loaded dendritic cells, and it is difficult to directly compare how each strategy influences immunogenicity 229 , 230 . In one trial that tested a multi-peptide vaccine that included up to 20 personal neoantigens, 4 of 6 patients with melanoma who entered the study with stage III disease experienced complete responses with no recurrence 25 months post vaccination, and the other 2 patients with progressive disease subsequently underwent anti-PD1 therapy that resulted in complete tumour regression 231 . Further, of the 97 different neoantigens that were tested for immunogenicity in this study, 60% elicited CD4 + T cell responses whereas 15% elicited CD8 + T cell responses. Another clinical trial, which tested an RNA vaccine that encoded 10 peptides representing personalized TAAs in 13 patients with advanced melanoma, achieved similar results 232 .

Healthy tissue and tumour tissue from a patient with cancer are submitted for DNA sequencing and bioinformatic analyses to identify gene variants that encode peptides that are specific to the tumour (neoantigens). Prediction algorithms are then used to screen for neoantigens that are likely to stably bind to the patient’s MHC (also known as HLA in human) molecules and their expression is validated by sequencing tumour mRNA. Multiple predicted neoantigens are then formulated into vaccines, which are administered to the patient together with adjuvants. Post treatment, the patient is regularly monitored for neoantigen-specific immune responses and tumour growth.

Pitfalls and adverse effects of cancer vaccines

Although these early cancer vaccine experiments have been promising, challenges remain. An individual tumour can harbour thousands of somatic mutations and predicting which neoantigens can elicit strong antitumour responses remains an imperfect art. However, the current methods, consisting of validating mRNA expression of the mutation in tumour cells and using software/databases to predict peptide–MHC binding, have been surprisingly effective in clinical trials to date 229 . However, this success has been biased towards MHC class I-specific neoantigens as prediction for MHC class II molecules presents unique challenges. For example, the increased diversity of MHC class II molecules and the structural nature of their open binding pocket make discerning a predictable binding motif difficult 233 . Taken together, these differences between MHC classes highlight the particular need for new MHC class II prediction algorithms. Other challenging factors to consider are the time and cost associated with developing bespoke vaccines. Currently, development and production of these vaccines takes approximately 4 months, and, although the downtime can be used to initiate other types of treatment, shortening the time span to personalized treatment is critical. For rapidly growing or metastatic tumours, months might matter. Ongoing efforts to improve design and manufacturing could shorten the production time to several weeks 229 .

Overall, the comprehensive identification of somatic mutations, and the evaluation of peptides derived from these mutations to elicit immune responses, has renewed interest in vaccination strategies for cancer treatment. Even though early clinical trials are promising, extrapolation of these findings could be misleading and advanced clinical trials will ultimately determine the efficacy of personalized vaccine therapy. Nonetheless, cancer vaccines are prototypical ‘single patient and single disease’ precision medications and would have been in the realm of science fiction just a few decades ago. Further research and technological developments will no doubt lead to greater precision and effectiveness and also provide a better understanding of the mechanisms of antitumoural immune responses.

Emerging cancer immunotherapeutics

The molecular diversity of genetic changes that transform cells in human cancers creates a plethora of diseases involving specific tissue types and cancer mechanisms. Given the exciting advances in cancer immunotherapy, various modifications to current immunotherapeutic approaches are being developed and tested to address the complexity of cancer immunopathogenesis and cancer targetability.

Combination therapies

Following the clinical success of checkpoint blockade monotherapy, combination therapies that couple agents with distinct mechanisms of action have augmented treatment success in various cancers. For example, ipilimumab and nivolumab combination therapy conferred a significant survival benefit in patients with metastatic melanoma and advanced renal cell carcinoma, leading to FDA approvals for these conditions 234 , 235 . The synergism of anti-CTLA4 and anti-PD1 therapies is not surprising because CTLA4 and PD1 regulate antitumoural immunity in a complementary manner 8 . Crosstalk between the CTLA4 and PD1 pathways, mediated by CD80 and PDL1 dimerization, provides additional insight into the mechanism behind the success of dual therapy 236 , 237 . However, as expected, combination checkpoint therapy also increases the risk of medication-induced toxicities 235 .

Combining radiation therapy with checkpoint blockade is another treatment option for recalcitrant tumours. The immunomodulatory effect of radiotherapy alone represents a double-edged sword. Mechanistically, radiotherapy increases the diversity of antitumoural T cell responses by exposing novel neoantigens at the same time as blunting the immune response through the induction of PDL1 expression on tumour cells 238 . Therefore, and on the basis of preclinical data, combining radiotherapy with blockers of the PD1 axis represents an attractive synergistic combination 239 . Patients with metastatic disease may represent a target population for deploying this combination as abscopal responses to radiotherapy are boosted by checkpoint blockade for many tumour types 238 , 240 . Overall, dual checkpoint blockade and radiation–checkpoint polytherapy represent promising avenues for synergistic therapeutic responses because these drug combinations display unique and complementary pharmacodynamics.

New targets for checkpoint blockade

Research is also directed at newly discovered negative regulators of T cell activation, including lymphocyte activation gene 3 (LAG3), T cell immunoglobulin 3 (TIM3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7-H3 and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT), as adjuvant cancer drugs 241 , 242 , 243 . LAG3 is an inhibitory ligand that reduces T cell activation by blocking CD4 contact sites on MHC class II proteins and is expressed on activated T cells and T reg cells. It prevents the overexpansion of the T cell compartment by inducing cell cycle arrest 244 . Like PD1, LAG3 is a marker of T cell exhaustion, which portends a poorer prognosis when expressed on TILs 245 . Multiple strategies of blockade have been developed, including a LAG3:Ig fusion protein and LAG3-targeted mAbs 246 . In clinical trials in patients with renal cell carcinoma and pancreatic adenocarcinoma, these drugs did not succeed as monotherapies even though they increased the frequency of tumour-specific T cells 246 . However, when combined with paclitaxel for metastatic breast cancer, 50% of patients treated with LAG3:Ig responded to treatment 247 . Recent research has demonstrated that fibrinogen-like protein 1 (FGL1) activates LAG3 independently of binding MHC class II molecules and interference with this interaction is essential for unleashing potent antitumoural effects 248 .

TIM3 is another negative regulator of the T cell response. Rather than inhibiting cell cycle progression like LAG3, it regulates apoptosis following galectin 9 binding 249 . Its upregulation could represent a mechanism of resistance to anti-PD1 therapy, making combination therapy an attractive option to boost the effectiveness of anti-PD1 therapy. In addition, TIM3 expression correlates with poor prognosis in non-small-cell lung cancer and follicular lymphoma, suggesting a role in cancer progression 250 . Similar to TIM3, VISTA is another molecule shown to be associated with resistance to current checkpoint inhibitors and has demonstrated synergism with anti-PD1 therapy in mouse models 251 , 252 .

B7-H3 represents another targetable negative regulator of the T cell response. It is highly expressed in many tumour types, including non-small-cell lung carcinoma, prostate cancer, pancreatic cancer, ovarian cancer and colorectal cancer 241 , 243 . Enoblituzumab, a humanized mAb targeting B7-H3, was effective at inducing antitumoural responses in a phase I study of patients with various tumour types 253 . Dual-affinity retargeting (DART) proteins that bind to B7-H3 and CD3, as well as radioactive iodine-conjugated B7-H3 mAbs, represent additional ways to modulate this pathway and are in early-phase clinical testing 254 , 255 .

Lastly, TIGIT, which contains two immunoreceptor tyrosine-based inhibitory motifs in its intracellular domain and dampens T cell hyperactivation, is being investigated as a checkpoint target. It is more robustly expressed in TILs than in peripheral cells, making it an attractive target owing to its increased specificity compared with other checkpoint molecules 243 . Preclinical evidence demonstrates that TIGIT blockade augments the effect of pre-existing checkpoint inhibitors and reinvigorates tumour-specific exhausted T cells 250 , 256 . Currently, blockade of immune checkpoints other than CTLA4 or the PD1 axis have not yet shown major clinical benefits as single agents but rather may increase the effectiveness of pre-existing treatments.

Although the blocking of immune checkpoint molecules releases potent antitumoural responses, the stimulation of T cell co-stimulatory receptors, including inducible co-stimulator (ICOS), tumour necrosis factor receptor superfamily member 4 (TNFRSF4; also known as CD134), tumour necrosis factor receptor superfamily member 9 (TNFRSF9; also known as 4-1BB), glucocorticoid-induced tumour necrosis factor receptor (GITR) and CD27, can also amplify the effect of existing immunotherapies, as shown preclinically and in early-stage clinical studies 168 , 170 , 171 , 241 , 242 , 243 , 257 . ICOS is a member of the CD28 family of co-stimulatory molecules that mediates context-dependent cytokine responses with an emphasis on T helper 2 (T H 2) cell skewing 258 . ICOS stimulation by vaccines modified to express ICOS ligand exhibited synergism with treatment with CTLA4-blocking antibodies preclinically 259 . ICOS upregulation following treatment with currently approved anti-CTLA4 and anti-PD1 therapies may represent a biomarker of active antitumoural responses because it associates with favourable outcomes 260 .

TNFRSF4 is another co-stimulatory molecule for which preclinical evidence indicates a role in deploying robust antitumoural responses in sarcoma, melanoma and breast cancer 261 , 262 . Data suggest that targeting TNFRSF4 amplifies anti-PD1 therapy because TNFRSF4 agonism can upregulate PDL1 expression 263 . In addition to synergism with checkpoint blockade, TNFRSF4 upregulation within CAR T cells by transfection represents a way to augment tumour cytotoxicity 170 . Agonism of additional TNFR family members, such as TNFRSF9, GITR and CD27, is being tested as adjuvant therapy in phase I/II trials for various tumour types, with promising results 243 . Therefore, agonism of positive T cell co-stimulatory signals, in concert with the existing checkpoint inhibitors or CAR T cells, represents a novel therapeutic avenue to boost antitumoural immunity.

Concluding remarks

Cancer immunotherapy focused on T cells has emerged as a powerful tool in the armamentarium against cancer. Nevertheless, it took many years of basic science discoveries and subsequent clinical translation to unequivocally demonstrate the power of modulating the immune system to treat cancer. Further research that investigates the regulation of T cells and other immune cells, for example APCs and natural killer cells, may allow us to enhance the power of this approach. In ‘difficult to treat’ tumours, the effect sizes observed in clinical trials of checkpoint blockade agents, ATC transfer therapies and cancer vaccines have been far higher than the most effective chemotherapeutic agents. Although immune-related adverse effects are common, these innovative immune-targeting therapies are better tolerated than traditional chemotherapeutic agents. The burgeoning field of cancer immunotherapy continues to grow as indications for currently approved therapies expand and the search for novel druggable targets continues. The cancer immunotherapy success stories we have recounted highlight the intrinsic connection between basic science research and clinical practice. They also illustrate how a bench-to-bedside approach, built upon a solid basic science foundation, can be successful in fighting one of humanity’s most dreaded diseases.

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Acknowledgements

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. A.D.W. was supported by the Emory University MD/PhD Program, NIH MD/PhD Partnerships Program and NIH Oxford–Cambridge Scholars Program. J.M.F. was supported by the Postdoctoral Research Associate Training Program of the National Institute of General Medical Sciences. The authors thank R. Kissinger for help with the illustrations. They thank G. De Luca for his support of A.D.W. as a DPhil co-mentor. They also thank Y. Zhang for invaluable editorial and scientific feedback. Lastly, the authors acknowledge and apologize to all researchers in this field who may have authored elegant studies that were not cited owing to space limitations.

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Antigens not expressed by self-tissues under normal conditions that manifest in the context of pathology; in cancer, these could be altered proteins/peptides encoded by mutated genes.

A mechanism of immune cell inhibition that restrains activation.

A group of proteins with genetic and structural similarities to antibodies.

(APCs). Immune cells involved in the uptake and processing of antigens to initiate cellular immune responses.

Soluble recombinant human cytotoxic T lymphocyte antigen 4 (CTLA4) fused to the immunoglobulin Fc domain that competes with endogenous CD28 for its ligands.

An interface between interacting lymphocytes and antigen-presenting cells that controls antigen-induced signalling.

A biological unit that comprises interacting lymphocytes and antigen-presenting cells.

A cytokine essential for lymphocyte activation, proliferation and tolerance.

An intracytoplasmic protein that facilitates molecular interactions and signal transduction.

The process by which antibody-based opsonization of target cells promotes their lysis by immune cytotoxic cells.

An albino inbred mouse strain commonly used in immunology research.

An inbred mouse stain with enhanced susceptibility to spontaneous development of type 1 diabetes mellitus.

A conserved amino acid sequence (TxYxx(V/I)) involved in both activation and inhibition of downstream signalling depending on the cell type and biological context.

A conserved amino acid sequence (S/I/V/LxYxxI/V/L) involved in the recruitment of inhibitory phosphatases to dampen downstream signalling.

The progressive loss of effector function due to chronic low-affinity antigen stimulation.

A phenomenon in which the therapeutic effect of radiation is extended beyond the boundaries of the tissue that was treated

Biasing of CD4 + T helper cells towards a phenotype essential for humoral immunity.

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Waldman, A.D., Fritz, J.M. & Lenardo, M.J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20 , 651–668 (2020). https://doi.org/10.1038/s41577-020-0306-5

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Root canal? Next-gen treatment could involve stem cells, not surgery

research news

UB faculty member Camila Sabatini’s research investigating novel biologically based avenues for tooth repair may reduce the need for root canals, a procedure in which the nerve of an infected tooth is removed and the canals are sealed with synthetic material.

By LAURIE KAISER

Published May 7, 2024

Camila Sabatini, associate professor of restorative dentistry in the School of Dental Medicine, has received the Harold Amos Medical Faculty Development Program (AMFDP) award from the Robert Wood Johnson Foundation to study novel therapies to repair damaged teeth.

The selective four-year, $420,000 grant will allow Sabatini to investigate strategies for the regeneration of tooth defects. She will work in collaboration with Techung Lee, associate professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences. Frank Scannapieco, SUNY Distinguished Professor of Oral Biology, will serve as adviser in this fellowship.

The award, traditionally reserved for promising physician-scientists to help them advance toward achieving a senior rank in academic medicine, expanded in scope to include dentistry in 2012 and nursing in 2015.

“As the only dentist in a cohort of 16 scholars selected this year, this award reflects her outstanding contributions to the field,” Scannapieco says.

Sabatini’s research investigating novel biologically based avenues for tooth repair may reduce the need for root canals and could potentially have major implications in the way dental care is rendered.

“Root canals happen when an infection has advanced to the nerve of the tooth,” Sabatini explains. “The nerve is removed, and the canals are sealed with a synthetic material. The loss of vitality weakens the tooth, making it prone to fracture.”

In this proposal, Sabatini says, the team will investigate ways to use stem cells of dental origin to promote the repair of damaged teeth, potentially avoiding the need for a root canal.

“Over the past two decades, scientists have come to rely on stem cells for tissue regeneration. We haven’t tapped into that nearly enough in dental medicine,” Sabatini notes. “The standard of care in dentistry today — fillings and implants — is still quite outdated, as it is based on the use of synthetic materials only. We are looking to increase our understanding of the biology of the host, so we can identify potential avenues for tissue repair.”

Cancer therapy drugs and gene therapy

The four-year grant will allow the team to investigate a drug-repurposing approach with an immunostimulant drug used in cancer therapy and a gene therapy strategy.

“The appeal of drug repurposing is the potential for immediate clinical translation, since phase I trials can be bypassed, moving directly to phase II trials,” Sabatini says. “Gene therapy could provide a cost-effective avenue for the healing of tooth defects.”

The therapies will be investigated using dental pulp stem cells obtained from extracted human molars and animal trials in mice, where artificially induced tooth defects will receive the various therapies. The animal studies proposed under this award could take the investigators a step closer to the next phase in the process of regulatory approvals of therapies and devices by the Food and Drug Administration (FDA).

“The possible impact of this research is profound,” Scannapieco says. “These innovative technologies have the potential to be widely applicable and cost-effective, ushering in a significant paradigm shift in dental care.”

Advancing team science, research-driven dental education

Sabatini joined the dental school in 2007 as a clinical assistant professor and was promoted to associate professor in 2015. She also currently serves as an adjunct professor of oral biology and of chemical and biological engineering.

A previous recipient of a National Institutes of Health (NIH) research award — in collaboration with Chong Cheng, professor, and Mark Swihart, SUNY Distinguished Professor and chair, both of the Department of Chemical and Biological Engineering — Sabatini has worked toward advancing a vision of team science and research-driven dental education.

“Embracing science at the core of dental education is the only path forward,” she says. “We, in academic centers, have a monumental task to evolve in our understanding of the profession and the factors that will influence the future workforce supply and demand.

“Understanding changes happening in dental practice will guide academic centers in meeting these demands. Several therapies will make their way into the profession over the next decade. Regenerative dentistry, while still in the early stages, will make its way into the mainstream as a non-invasive treatment option.”

Sabatini’s AMFDP award followed a competitive peer-reviewed process with members of a national advisory committee affiliated with such agencies as the American Heart Association and the National Institute of Diabetes and Digestive and Kidney Diseases, among others.

“I am thrilled about this opportunity,” Sabatini says. “I look forward to continuing to build my research program, expanding into the field of regenerative medicine and contributing to the NIH-funded pool of dentist/scientists for the advancement of this work.”

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The 150 most important questions in cancer research and clinical oncology series: questions 94–101

Cancer Communications

Question 94: The origin of tumors: time for a new paradigm?

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Question 95: How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma?

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Question 96: Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor?

Question 97: What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction?

Question 98: Is high local concentration of metformin essential for its anti-cancer activity?

Question 99: How can we monitor the emergence of cancer cells anywhere in the body through plasma testing?

Question 100: Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells?

Question 101: Is cell migration a selectable trait in the natural evolution of carcinoma?

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Features of normal cells

Cancer cells don't stop growing and dividing

02_how_cancer_cells_keep_on_reproducing_to_form_a_tumour_1.svg

Cancer cells ignore signals from other cells

Cancer - When cells cause cancer by giving the wrong messages - Cancer Research UK

Cancer cells don't stick together

34_diagram_showing_a_cancer_cell_which_has_lost_its_ability_to_stick_to_other_cells.svg

Cancer cells don't specialise

Cancer cells don't repair themselves or die

Cancer cells look different

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International Scholar Feature: Cancer immunotherapy research spans departments, continents

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