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. Immunotherapy resistance This resistance can be caused by a type of cell called a cancer-associated … This new treatment h...as been shown to be effective for Stage 4 melanoma patients, raising the long term survival rate to 40% from lesser than 10% previously. We spoke with Cole and his mother, Denise, about growing up with cancer, exploring treatment options, advocating for immunotherapy, and sharing his story. Cancerous cells also have the ability to “activate” fibroblasts, turning them into CAFs. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. 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. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Effectively, CAFs protect tumours from attack by the immune system by developing a defensive shield around the tumour. With immunotherapy, “our job is to redirect the immune response,” he said. 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. In this type of treatment, the body’s own immune system is recruited to fight the disease by recognising and attacking ‘foreign’ cancer cells. 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 By targeting coinhibitory and costimulatory receptors in the immune system, it is possible to counteract the pathways that tumors utilize to avoid immune destruction. To do this, the researchers used a variety of experimental techniques, including mouse models specifically developed by this research group, to more accurately reflect the CAF properties of human tumours. To overcome the developed resistance to immunotherapy, chemotherapy with nedaplatin plus paclitaxel in addition to nivolumab was administered and a progression-free survival (PFS) of 5 months was achieved. 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. With the high rate of clinical response to several of these therapies, along with early data indicating that combination immunotherapies may be even more potent, it seems likely that effective immune-based therapies will become a reality for patients with a range of different cancers that physiologically support the T-cell-inflamed tumor microenvironment in a subset of individuals. For example, CAFs trigger cancers to grow more rapidly and spread, and recent studies have shown that CAF shield tumours from immune attack. 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. Lung cancer is considered to cause the most cancer‐related deaths worldwide. The researchers stressed, however, that TOX isn’t a lone wolf. 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. So approaches like CAR T-cell therapy, where you can genetically engineer effector T cells in the laboratory, she continued, may be the best option for translating these findings into new treatments. However, we, found that targeting TGF-ꞵ did not normalise the CAF phenotype or reduce CAF levels in tumours. In the Penn-led study, for example, the researchers showed that TOX interacts with several specific enzymes involved in opening and closing chromatin.Â. You can change your preferences or unsubscribe by clicking the unsubscribe link in the footer of any email you receive from us, or by contacting us at audience@researchoutreach.org at any time and if you have any questions about how we handle your data, please review our privacy agreement. Dr. McCarthy agreed. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Available at: https://researchoutreach.org/articles/overcoming-resistance-to-cancer-immunotherapy/ (Accessed YYYY/MM/DD). Suite 25 Westend Office Suites 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. The tumour-protective power of CAFs was effectively eliminated, allowing CD8+ T-cells to enter tumours and kill their target cells. 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. Gareth Thomas is Professor of Experimental Pathology at the University of Southampton and a Consultant in Cellular Pathology. This finding was proven by the final stage of the study: combining Setanaxib with several different currently-available immunotherapies, including anti-tumour vaccination and anti-PD1 checkpoint therapy. An exhausted T cell with TOX (blue) in the nucleus. 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. Approaches to Address Primary Resistance Siwen Hu-Lieskovan, MD, PhD - Huntsman Cancer Institute, University of Utah : 10:55 a.m. 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. But studies have suggested that blocking the activity of checkpoint proteins in exhausted T cells doesn’t achieve that end. E: audience@researchoutreach.org. Are there other potential targets for blocking the activity of CAFs? Both drugs, evolocumab (Repatha) and alirocumab (Praluent), appear to improve the immunotherapy drugs’ ability to find tumors. 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 … Below you can select how you’d like us to interact with you and we’ll keep you updated with our latest content. CD8+ T-cells are important effectors of the immune system and are responsible for killing cancer cells; most current immunotherapies depend on the ability of CD8+ T cells to infiltrate tumours effectively. J Natl Cancer Inst. Overcoming Cancer’s Financial Toxicity with Real-World Data. by NCI Staff, September 24, 2020, Below you can select how you’d like us to interact with you and we’ll keep you updated with our latest content. 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. 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. 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. Finding routes for lymphocytes to enter tumours is therefore a key goal for some scientists working on immunotherapy, as it could greatly increase the number of patients who could benefit from this treatment. In the mouse models, artificially-created high levels of CAFs led to immunotherapy resistance, as the lymphocytes were unable to successfully penetrate the tumour. 2018. While the immune system is effective against a huge range of infective diseases, cancer cells have developed sophisticated ways of avoiding immune destruction. Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. Cholesterol-lowering drugs known as PCSK9 inhibitors may improve the effectiveness of cancer immune checkpoint inhibitors, according to studies in mice. This resistance can be caused by a type of cell called a cancer-associated fibroblast, which builds protective The team discovered that CAFs function by specifically excluding a group of lymphocytes, CD8+ T cells, from tumours (another type, CD4+ T cells, are able to enter). Â. 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. Therapies that affect the behavior of these transcription factors is “how you think about potentially flipping [the T cell] to another state,” she said. 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. NOX4 – the key to neutralising CAFs? This helps us improve how our site works and ensures we offer you the best content. Can Some Women Treated for Endometrial Cancer Forgo Radiation after Surgery? Authors: Kathy Madden, FNP, AOCNP, APHN; Suzanne McGettigan, MSN, CRNP, AOCN; Krista M. Rubin, MS, FNP-BC CE Released: 11/11/2016 THIS ACTIVITY HAS EXPIRED; Valid … Towards more successful immunotherapy This is likely due to the fact that not all CAFs are the same; in fact, they are a heterogeneous group of cells that share certain features, with some CAFs even shown to suppress tumour growth. 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. 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. In their recent study, the team built on this discovery by using the drug Setanaxib, a NOX4 inhibitor, to inhibit CAF activation. In a previous study, Dr. Rao’s group found that NR4A transcription factors are found at high levels in exhausted T cells. CXCL12 expression by CAF can mediate immunotherapy resistance, and inhibiting its receptor (CXCR4) has been shown to improve response to checkpoint therapy. But taking out TOX and TOX2 may not be the only means to the same end, Dr. Rao said. ... we reported on RWD on 105 patients on the onset of FT during their immunotherapy treatments. 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. “That’s a strong demonstration of how [removing] a different transcription factor can do almost exactly the same thing,” she said.Â. Uncontrolled activation of fibroblasts results in tissue fibrosis, including organ fibrosis and atherosclerosis, and it is thought that around 45% of deaths are related to fibrosis in some form or another. 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. United Kingdom 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. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4. 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. By selecting any of the topic options below you are consenting to receive email communications from us about these topics. Understanding the events that control T-cell exhaustion “allows us to get a better handle on how to do that.”. September 15, 2020. Stage 4 cancer patients may gain new hope with immunotherapy, a new form of treatment that fights cancer with the body’s own immune system. 24 True success in this realm may be achieved with the identification of a pan-cancer … 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. In her group’s earlier study, CAR T cells that lacked NR4A were also much more effective than unaltered CAR T cells in the same mouse model of melanoma. One of the challenges is that pancreatic cancer tumors don’t typically respond to immunotherapy. Targeting cancer-associated fibroblasts Unfortunately, most patients (around 80%) fail to respond to this type of treatment. Break: Session II: Primary Resistance 10:30 a.m. T cells don’t come in only one flavor. 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. Hanley CJ, et al. 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. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. 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. 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. Cancer immunotherapy relies on getting T cells—the immune system’s primary killers of infected and diseased cells—to attack and kill tumor cells. 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. 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. Already, two immunotherapies have been approved by the U.S. Food and Drug Administration (FDA) for subsets of patients with advanced liver cancer. In the relatively near future, these discoveries could benefit many cancer patients, some of whom may currently have few alternative treatment options. For details, see our, https://doi.org/10.1038/s41568-019-0238-1, https://biorxiv.org/cgi/content/short/2020.06.08.134270v1, https://researchoutreach.org/articles/overcoming-resistance-to-cancer-immunotherapy/, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, Neuronal cultures to study the brain and neurological disorders. 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. T: +44 1453 827 934 In fact, she said the studies’ findings support the idea that T cells becoming exhausted “is not just a stage or unfortunate consequence.” Rather, exhausted T cells are “a separate lineage” of T cell that still have a role to play. Revealing the role of CAFs “While immunotherapy is eliciting remarkable responses against some tumor types, the same immune-based approaches are not working well in ovarian cancer or other cancers that are more aggressive,” says Dr. Cubillos-Ruiz. Professor Gareth Thomas of the University of Southampton leads a research team focusing on a particular type of cell called cancer-associated fibroblasts (CAFs). (117). In recent work, Professor Thomas and his team investigated exactly how CAFs regulate immunotherapy resistance and identified a therapy to overcome this. Setanaxib has several other advantages that make it an excellent choice for further investigation as a cancer treatment: it has already been tested in several clinical trials for fibrotic conditions (kidney, liver lung fibrosis; NCT03226067, NCT02010242), and is known to be extremely safe; it is also simple to administer, and effective, when taken orally. Normally, immune cells (or lymphocytes) called T-cells would eliminate abnormal cells – however, many cancers “block” this process and have developed different mechanisms to shield them from immune attack. Researchers have successfully developed blocking antibodies against two immune checkpoint proteins, CTLA4 and PD1/PDL-1. We use MailChimp as our marketing automation platform. Currently, the most successful immunotherapies use antibodies directed against ‘immune checkpoints’ found on T-cells. Until now, treatments that target CAFs as part of cancer therapy have been unsuccessful. 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, Stonehouse Exhaustion happens “for a reason,” Dr. Schietinger said in a news release, “to prevent the [T] cells from getting overstimulated and dying.”. When this regulation goes wrong, it can result in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. “These tumors, especially in ovarian and pancreatic cancer, are extremely immuno-suppressive. 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.”. All the groups found that one of the biggest differences in expression was seen with the gene for TOX, which was consistently expressed at very high levels in exhausted T cells but at very low levels in effector and memory T cells. Much of the research involved work done in lab studies and mouse models, so more research is needed to better understand the extent to which TOX and these other proteins influence T-cell exhaustion in people with cancer, said John Wherry, Ph.D., director of the Institute for Immunology at the University of Pennsylvania, who led one of the Nature studies. 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. 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. Whether certain regions of chromatin are open or closed can affect which proteins are ultimately produced in a cell and, thus, a cell’s behavior. Cancer immunotherapy has largely been hindered by the ability of tumors to induce tolerance and escape the immune system. T cells don’t come in only one flavor. Jaffee also leads the Stand Up To Cancer-Lustgarten Foundation Dream Team project called “Transforming Pancreatic Cancer to a Treatable Disease.” Overcoming Challenges. 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. They found that the drug prevents CAF differentiation (the process by which a cell develops into a more specialised type). In some forms of cancer, such as lung cancer and melanoma (a type of skin cancer), immunotherapy is already a common treatment. Share: You can copy and redistribute the material in any medium or format, Your email address will not be published. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression … 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. Would you like to learn more about our services? NOX4 inhibition was able to both prevent and reverse CAF formation in mouse tumours, triggering a fundamental change in the environment surrounding the tumour. by NCI Staff, October 14, 2020, Several of the studies, in fact, tested what would happen if they eliminated TOX in T cells. TGF-ꞵ signalling is central to CAF differentiation and TGF-ꞵ1-neutralising antibodies can promote response to αPD-L1 immunotherapy. 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. The team are currently investigating how CAF produce this effect, examining how CAF affect T-cell function and movement. Effector T cells, for instance, immediately seek out and destroy specific threats, like virus-infected cells or tumor cells. Required fields are marked *, Research Outreach Dr. Rao’s group, meanwhile, took a different approach, engineering CAR T cells to lack both TOX and TOX2. The Nurse View: Overcoming Challenges Associated with Cancer Immunotherapy. Although most inflammatory toxicities resolve with systemic immune suppression, fatal toxicities can occur, and interruption and discontinuation of immunotherapy because of toxicity … Many cancer patients who receive PD-1 blockade therapy do not respond to it, developing resistance. Thank you for expressing interest in joining our mailing list and community. Overcoming resistance to cancer immunotherapyResearch OUTREACH. Westend 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. Cancer vaccines have shown promising results as a means of personalizing cancer immunotherapy and potentially enhancing immune memory in a minority of patients. In another of the Nature studies, a team led by researchers from the Technical University of Munich in Germany and St. Jude Children’s Research Hospital in Tennessee showed that TOX appeared to be essential for the formation of exhausted T cells.Â. 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. Immunotherapy is one of the most exciting developments in cancer treatment in recent years. doi: 10.1093/jnci/djx121. 110(1). Overcoming resistance to cancer immunotherapy. Despite the exciting potential of immunotherapy, CAF-rich tumours respond poorly to current treatments, resulting in immunotherapy resistance in a large majority of patients. These antibodies effectively remove one of the tumour’s key defences and allow the immune system to attack the cancerous cells. The combination of Setanaxib with immunotherapy was able to promote the immunotherapy response in CAF-laden tumours that were previously resistant to the treatment. Immunotherapy Primary and Acquired Resistance Antoni Ribas, MD, PhD - University of California Los Angeles: 10:15 a.m. Even more significantly, they discovered that Setanaxib can “normalise” previously-established CAFs, so that they behave more like a normal fibroblast. One hallmark of exhausted T cells is the increased appearance on their surface of checkpoint proteins like PD-1 and CTLA-4, which can cause those T cells to stand down. It seems that, in many of these cases, lymphocytes get “stuck” at the edge of the tumour, and so are unable to infiltrate into the cancer and destroy the target cells. 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 goals of immunotherapy is to identify and target these mechanisms so that immune cells can function correctly and destroy cancerous cells. In 2006, Cole was diagnosed with acute lymphoblastic leukemia (ALL). These cells are found in large numbers in many types of tumour cancer and affect tumour development in multiple different ways. 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. His team investigated exactly how CAFs regulate immunotherapy resistance can be effectively overcome through NOX4 restored. How CAFs regulate immunotherapy resistance can be effectively overcome through NOX4 inhibition restored immunotherapy response in tumors. If you are happy for us to interact with you and we’ll keep you with. Large numbers in many types of tumour cancer and affect tumour development in multiple different ways “normalise”... Researchers have successfully developed blocking antibodies against two immune checkpoint proteins in exhausted T cell with TOX ( ). 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