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Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. And in the PNAS study, a research team led by Anjana Rao, Ph.D., of the La Jolla Institute for Immunology in California, showed that there was a strong interdependence among TOX and a related protein, TOX2, as well as several other transcription factors, including a family of them called NR4A, and one called NFAT. This can be done in a couple of ways: Stimulating, or boosting, the natural defenses of your immune system so it works harder or smarter to find and attack cancer cells. While the immune system is effective against a huge range of infective diseases, cancer cells have developed sophisticated ways of avoiding immune destruction. Effector T cells, for instance, immediately seek out and destroy specific threats, like virus-infected cells or tumor cells. A significant proportion of cancers are CAF-rich; these usually behave aggressively and are associated with poor patient survival. Primary and acquired resistance to immunotherapy necessitates novel strategies that can overcome cellular processes and genetic mutations of resistance to advance into the next age of cancer therapy. And that’s important, because so-called hot tumors, those that are loaded with immune cells and thus should be ideal candidates to respond to immunotherapy, “are often just full of exhausted T cells,” Dr. Wherry explained. by NCI Staff, Credit: John Wherry, Ph.D., Penn Medicine, Complementary & Alternative Medicine (CAM), Coping with Your Feelings During Advanced Cancer, Emotional Support for Young People with Cancer, Young People Facing End-of-Life Care Decisions, Late Effects of Childhood Cancer Treatment, Tech Transfer & Small Business Partnerships, Frederick National Laboratory for Cancer Research, Milestones in Cancer Research and Discovery, Step 1: Application Development & Submission, essential for the formation of exhausted T cells, there was a strong interdependence among TOX and a related protein, TOX2, NR4A transcription factors are found at high levels, specific enzymes involved in opening and closing chromatin, approved by the Food and Drug Administration to treat leukemia and lymphoma, Researchers Testing “Packaged” CAR T Cells for Retinoblastoma, Study Confirms HPV Vaccine Prevents Cervical Cancer, NCI Priorities in Reducing Global Cancer Burden, U.S. Department of Health and Human Services. The researchers stressed, however, that TOX isn’t a lone wolf. In the relatively near future, these discoveries could benefit many cancer patients, some of whom may currently have few alternative treatment options. Exhaustion happens “for a reason,” Dr. Schietinger said in a news release, “to prevent the [T] cells from getting overstimulated and dying.”. “That’s a strong demonstration of how [removing] a different transcription factor can do almost exactly the same thing,” she said.Â. NOX4 inhibition was able to both prevent and reverse CAF formation in mouse tumours, triggering a fundamental change in the environment surrounding the tumour. Evidence from several of the studies points to epigenetic mechanisms—that is, changes to the structure of chromatin, the molecular packaging for genetic material in the nucleus of cells. For example, CAFs trigger cancers to grow more rapidly and spread, and recent studies have shown that CAF shield tumours from immune attack. Recent studies using single cell RNA sequencing have shed some light on CAF heterogeneity, and identified different CAF subpopulations, but up to this point, the lack of understanding of CAF phenotype, function and regulatory mechanisms have made targeting CAF difficult and resulted in a lack of specific therapeutic targets. By clicking below to submit this form, you acknowledge that the information you provide will be transferred to MailChimp for processing in accordance with their Privacy Policy and Terms. TGF-ꞵ signalling is central to CAF differentiation and TGF-ꞵ1-neutralising antibodies can promote response to αPD-L1 immunotherapy. Immunotherapy treatments that unleash the immune system’s ability to fight cancer offer a promising new avenue through which doctors can potentially improve outcomes for patients with liver cancer. Cancer vaccines have shown promising results as a means of personalizing cancer immunotherapy and potentially enhancing immune memory in a minority of patients, such as NY-ESO-1 cancer vaccines.117 118 True success in this realm may be achieved with the identification of a pan-cancer antigen that can be targeted through vaccination. Overcoming resistance to cancer immunotherapy Immunotherapy, which uses the body's own immune system to fight cancer, is a great step forward in cancer treatment. There are different populations of T cells with different functions, even within the subset known as cytotoxic T cells, whose primary job is to kill problematic cells. Immunotherapy is part of a class of treatments known as biological therapies, which use substances made from living organisms, such as immune cells and antibodies, to treat disease. Identifying mechanisms by which CAF modulate tumour immune evasion could be a therapeutic strategy. Researchers have successfully developed blocking antibodies against two immune checkpoint proteins, CTLA4 and PD1/PDL-1. CANCER RESEARCH | TRANSLATIONAL SCIENCE NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors A C Kirsty Ford1, Christopher J. Hanley1, Massimiliano Mellone1, Cedric Szyndralewiez2, Freddy Heitz2, Philippe Wiesel2, Oliver Wood1, Maria Machado1, Maria-Antoinette Lopez1, Anusha-Preethi Ganesan3, One of the challenges is that pancreatic cancer tumors don’t typically respond to immunotherapy. Suite 25 Westend Office Suites Checkpoint blockade immunotherapy has led to impressive therapeutic responses in a wide variety of tumors, but also leads to a spectrum of inflammatory toxicities that can involve any organ system in the body. An exhausted T cell with TOX (blue) in the nucleus. Research groups from around the globe have now identified several proteins that appear to play a central role in transforming T cells from powerful destroyers to depleted bystanders with limited capacity to harm cancer cells. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. Many cancer patients who receive PD-1 blockade therapy do not respond to it, developing resistance. The team are currently investigating how CAF produce this effect, examining how CAF affect T-cell function and movement. Results from a Phase II trial led by researchers at The University of Texas MD Anderson Cancer Center suggest that a combination of ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) can generate durable responses in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC), an “immune-cold” cancer that does not typically respond well to immunotherapy. It works with several other transcription factors—whose primary function is to help turn genes on and off—to orchestrate the exhaustion “program” in T cells.Â. To learn more about the development of T cell exhaustion, each of the four studies analyzed the differences in the genes and proteins found in cytotoxic T cells, using experiments that replicate viral infections and tumor development. There are different populations of T cells with different functions, even within the subset known as cytotoxic T cells, whose primary job is to kill problematic cells. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Required fields are marked *, Research Outreach For other tumour types, researchers are continuing to investigate ways to optimise the therapy, so that it can be used to improve the survival of many more cancer patients. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Share: You can copy and redistribute the material in any medium or format, Your email address will not be published. Your email address will not be published. 2018. (117). In the Penn-led study, for example, the researchers showed that TOX interacts with several specific enzymes involved in opening and closing chromatin.Â. Unfortunately, as it was unknown how exactly his treatment worked, his methods were shunned by oncologists, who went on to make surgery and radiotherapy the standards for treating cancer in the 20th century. J Natl Cancer Inst. Cancer immunotherapy has largely been hindered by the ability of tumors to induce tolerance and escape the immune system. Cancer vaccines have shown promising results as a means of personalizing cancer immunotherapy and potentially enhancing immune memory in a minority of patients. But if additional studies confirm the role of TOX and the other transcription factors in controlling T-cell exhaustion, he added, it could open up potential strategies for boosting the effectiveness of cancer immunotherapies. Overcoming resistance to cancer immunotherapy. Are there other potential targets for blocking the activity of CAFs? by NCI Staff, September 24, 2020, The combination of Setanaxib with immunotherapy was able to promote the immunotherapy response in CAF-laden tumours that were previously resistant to the treatment. Understanding the events that control T-cell exhaustion “allows us to get a better handle on how to do that.”. The fact that TOX affects chromatin in this manner is important from the perspective of translating these findings into potential therapeutic approaches, said Susan McCarthy, Ph.D., of NCI’s Division of Cancer Biology. GL10 3FA When Dr. Schietinger and her colleagues introduced T cells engineered to lack the gene for TOX into mice with tumors, they found that, far from becoming powerful killers of cancer cells, the T cells died off.Â, The findings, they wrote, support the idea that T cell exhaustion is not an immune system shortcoming, but a biological self-defense mechanism. Overcoming resistance to cancer immunotherapyResearch OUTREACH. Unfortunately, however, it is currently ineffective in most patients. Lung cancer is considered to cause the most cancer‐related deaths worldwide. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. Hanley CJ, et al. When they used the engineered CAR T cells to treat mice with established melanoma tumors, the treatment was far more effective than standard CAR T cells or those lacking only TOX or TOX2. Dr. Rao’s group, meanwhile, took a different approach, engineering CAR T cells to lack both TOX and TOX2. Approaches to Address Primary Resistance Siwen Hu-Lieskovan, MD, PhD - Huntsman Cancer Institute, University of Utah : 10:55 a.m. Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Due to the deficiency in early‐stage diagnostics and local invasion or distant metastasis, the first line of treatment for most patients unsuitable for surgery is chemotherapy, targeted therapy or immunotherapy. Would you like to learn more about our services? So if researchers are going to succeed in making immunotherapy treatments like checkpoint inhibitors more effective in more patients, he said, exhausted T cells are “a prominent T-cell population that we need to understand better.”. Immune checkpoint proteins act as natural regulators of the immune system; they inhibit T-cell function, acting as brakes to prevent immune responses from getting out of control and attacking normal cells indiscriminately. A series of recent studies—including three published June 17 in Nature and one initially published May 31 in PNAS—largely zeroed in on one protein in particular, a transcription factor called TOX. September 15, 2020. Stonehouse Doctors thought for a long time that immunotherapy wouldn’t work for non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), the two most common types. Moreover, TGF-ꞵ1 is a pleiotropic cytokine with roles in tissue homeostasis and tumour suppression, and global TGF-ꞵ1 targeting is therefore a potentially risky strategy. But when the immune system is forced to be active for extended periods, such as with persistent viral infections or the progressive development of cancer, effector T cells can run out of steam. Those changes altered the accessibility of chromatin to transcription factors and other components of the transcription machinery. Thank you for expressing interest in joining our mailing list and community. Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. Already, two immunotherapies have been approved by the U.S. Food and Drug Administration (FDA) for subsets of patients with advanced liver cancer. Westend In a critical step towards more successful immunotherapy, the team showed that CAFs are not fixed in their final form, but need the continuous activity of NOX4 to maintain their activated state. Several strategies have been designed to overcome these hurdles: the identification and combination of known and new antigens, together with the combination of immunotherapeutic and classical approaches may overcome cancer immune evasion. United Kingdom However, cancer cells take advantage of this system, by stimulating the immune checkpoints on T-cells; this dampens the T-cell response and protects the cancer cell from attack. The researchers tested the effects of CAFs on different types of immunotherapy, including vaccination and checkpoint inhibition, as well as examining how CAFs affect the function of different types of immune cell. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. Dr. McCarthy agreed. CAFs protect tumours from attack by the immune system by triggering the development of a defensive shield around the tumour. In the case of permitted digital reproduction, please credit the National Cancer Institute as the source and link to the original NCI product using the original product's title; e.g., “Improving Cancer Immunotherapy: Overcoming the Problem of ‘Exhausted’ T Cells was originally published by the National Cancer Institute.”, November 10, 2020, Cancerous cells also have the ability to “activate” fibroblasts, turning them into CAFs. Some effector T cells eventually develop, or differentiate, into memory T cells, which can permanently linger in the body to be quickly marshaled if the same threat should ever reappear. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Thank you for expressing interest in joining our mailing list and community. Thomas G., (2020). But studies have suggested that blocking the activity of checkpoint proteins in exhausted T cells doesn’t achieve that end. Jaffee also leads the Stand Up To Cancer-Lustgarten Foundation Dream Team project called “Transforming Pancreatic Cancer to a Treatable Disease.” Overcoming Challenges. Checkpoint blockade immunotherapy revolutionizes the field of cancer therapy in clinic. The Nurse View: Overcoming Challenges Associated with Cancer Immunotherapy. Cancer immunotherapy relies on getting T cells—the immune system’s primary killers of infected and diseased cells—to attack and kill tumor cells. Some effector T cells eventually develop, or differentiate, into memory T cells, which can permanently linger in the body … In one of the Nature studies, a research team led by Andrea Schietinger, Ph.D., from Memorial Sloan Kettering Cancer Center, showed that, in lab models of a new viral infection, TOX levels remained low. Immunotherapy Primary and Acquired Resistance Antoni Ribas, MD, PhD - University of California Los Angeles: 10:15 a.m. Targeting cancer-associated fibroblasts The tumour-protective power of CAFs was effectively eliminated, allowing CD8+ T-cells to enter tumours and kill their target cells. E: audience@researchoutreach.org. Cancer immunotherapies that activate both killer T cells and helper T cells may boost the effectiveness of checkpoint inhibitors and cancer vaccines, and benefit a larger percentage of cancer … Although most inflammatory toxicities resolve with systemic immune suppression, fatal toxicities can occur, and interruption and discontinuation of immunotherapy because of toxicity … But once the infection became more chronic, TOX levels spiked and remained high. Can Some Women Treated for Endometrial Cancer Forgo Radiation after Surgery? Immunotherapy is one of the most exciting developments in cancer treatment in recent years. Research led by a team from Roswell Park Comprehensive Cancer Center details a promising new strategy for overcoming resistance to immunotherapy by zeroing in o We spoke with Cole and his mother, Denise, about growing up with cancer, exploring treatment options, advocating for immunotherapy, and sharing his story. By targeting coinhibitory and costimulatory receptors in the immune system, it is possible to counteract the pathways that tumors utilize to avoid immune destruction. One of the goals of immunotherapy is to identify and target these mechanisms so that immune cells can function correctly and destroy cancerous cells. But there’s an important stumbling block for immunotherapy: T cells’ ability to kill can fade, a phenomenon often referred to as exhaustion.Â. Back in 1891 the father of immunotherapy, William B. Coley, found that injecting cancerous tumors with inactivated live bacteria could send cancer into complete remission. In fact, she stressed, in all of the studies of exhausted T cells her group has been involved in, TOX, TOX2, and NR4A transcription factors were all well represented “over and over again.”, So how do TOX and these other transcription factors cause exhaustion?Â. 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