But few proteins can act alone. 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. We are able share your email address with third parties (such as Google, Facebook and Twitter) in order to send you promoted content which is tailored to your interests as outlined above. 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. 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. In some forms of cancer, such as lung cancer and melanoma (a type of skin cancer), immunotherapy is already a common treatment. Dr. McCarthy agreed. 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. 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. Â. Immune checkpoint inhibitors block these checkpoint proteins and, in so doing, can rev up the immune response against 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. We use cookies to gather data about how you use our site. 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. Currently, the most successful immunotherapies use antibodies directed against ‘immune checkpoints’ found on T-cells. These antibodies effectively remove one of the tumour’s key defences and allow the immune system to attack the cancerous cells. In their recent study, the team built on this discovery by using the drug Setanaxib, a NOX4 inhibitor, to inhibit CAF activation. Approaches to Address Primary Resistance Siwen Hu-Lieskovan, MD, PhD - Huntsman Cancer Institute, University of Utah : 10:55 a.m. But there’s an important stumbling block for immunotherapy: T cells’ ability to kill can fade, a phenomenon often referred to as exhaustion.Â. The researchers stressed, however, that TOX isn’t a lone wolf. In this type of treatment, the body’s own immune system is recruited to fight the disease by recognising and attacking ‘foreign’ cancer cells. 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. J Natl Cancer Inst. In previous work, Professor Thomas and his colleagues demonstrated that NOX4 triggers CAF activation in human cancers. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. by NCI Staff, October 14, 2020, The tumour-protective power of CAFs was effectively eliminated, allowing CD8+ T-cells to enter tumours and kill their target cells. 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, A significant proportion of cancers are CAF-rich; these usually behave aggressively and are associated with poor patient survival. Overcoming resistance to cancer immunotherapyResearch OUTREACH. Effector T cells, for instance, immediately seek out and destroy specific threats, like virus-infected cells or tumor cells. This resistance can be caused by a type of cell called a cancer-associated … 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. Several of the studies, in fact, tested what would happen if they eliminated TOX in T cells. Jaffee also leads the Stand Up To Cancer-Lustgarten Foundation Dream Team project called “Transforming Pancreatic Cancer to a Treatable Disease.” Overcoming Challenges. CXCL12 expression by CAF can mediate immunotherapy resistance, and inhibiting its receptor (CXCR4) has been shown to improve response to checkpoint therapy. Cancerous cells also have the ability to “activate” fibroblasts, turning them into CAFs. But taking out TOX and TOX2 may not be the only means to the same end, Dr. Rao said. Results and conclusion The LELC patient progressed after first-line chemotherapy, was treated by immunotherapy alone and progressed again. Professor Thomas and his colleagues believe that targeting CAFs with NOX4 inhibitors, as successfully demonstrated in their research, offers hope for more effective treatment of a wide range of cancers. 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. How Immunotherapy Is Used to Treat Cancer. 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. Revealing the role of CAFs In the mouse models, artificially-created high levels of CAFs led to immunotherapy resistance, as the lymphocytes were unable to successfully penetrate the tumour. Immunotherapy, which uses the body’s own immune system to fight cancer, is a great step forward in cancer treatment. 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. 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. In the relatively near future, these discoveries could benefit many cancer patients, some of whom may currently have few alternative treatment options. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. Many cancer patients who receive PD-1 blockade therapy do not respond to it, developing resistance. In recent work, Professor Thomas and his team investigated exactly how CAFs regulate immunotherapy resistance and identified a therapy to overcome this. Various nanosized drug delivery systems (NDDS) have been fabricated to enhance the therapeutic benefits of anti-PD drugs or enable combined anti-PD therapies for more effective cancer immunotherapy. 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. 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. In 2006, Cole was diagnosed with acute lymphoblastic leukemia (ALL). September 15, 2020. 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. However, we, found that targeting TGF-ꞵ did not normalise the CAF phenotype or reduce CAF levels in tumours. “These tumors, especially in ovarian and pancreatic cancer, are extremely immuno-suppressive. 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. Thank you for expressing interest in joining our mailing list and community. 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. 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. 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. An exhausted T cell with TOX (blue) in the nucleus. Unfortunately, however, it is currently ineffective in most patients. Westend GL10 3FA Significance: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4. Dr. Rao’s group, meanwhile, took a different approach, engineering CAR T cells to lack both TOX and TOX2. United Kingdom Stonehouse T cells don’t come in only one flavor. 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. TGF-ꞵ signalling is central to CAF differentiation and TGF-ꞵ1-neutralising antibodies can promote response to αPD-L1 immunotherapy. Cholesterol-lowering drugs known as PCSK9 inhibitors may improve the effectiveness of cancer immune checkpoint inhibitors, according to studies in mice. 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. Required fields are marked *, Research Outreach Break: Session II: Primary Resistance 10:30 a.m. If you are happy for us to contact you in this way, please tick below. 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, Metastatic Colorectal Cancer May Spread Early in the Disease, Study Finds, If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance about copyright and permissions. Identifying mechanisms by which CAF modulate tumour immune evasion could be a therapeutic strategy. The CAR T cells they used were otherwise similar to the two therapies already approved by the Food and Drug Administration to treat leukemia and lymphoma. While the immune system is effective against a huge range of infective diseases, cancer cells have developed sophisticated ways of avoiding immune destruction. Even more significantly, they discovered that Setanaxib can “normalise” previously-established CAFs, so that they behave more like a normal fibroblast. 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. These cells are found in large numbers in many types of tumour cancer and affect tumour development in multiple different ways. 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. The team are currently investigating how CAF produce this effect, examining how CAF affect T-cell function and movement. 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. 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 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. Immunotherapy is one of the most exciting developments in cancer treatment in recent years. Both drugs, evolocumab (Repatha) and alirocumab (Praluent), appear to improve the immunotherapy drugs’ ability to find tumors. By selecting any of the topic options below you are consenting to receive email communications from us about these topics. Cancer immunotherapy has largely been hindered by the ability of tumors to induce tolerance and escape the immune system. Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. 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 … 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. 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 … 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. 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. From a practical standpoint, developing drugs that can manipulate the transcriptional machinery of already exhausted T cells in the body may be particularly challenging, Dr. McCarthy said. Thomas G., (2020). We use MailChimp as our marketing automation platform. Share: You can copy and redistribute the material in any medium or format, Your email address will not be published. This resistance can be caused by a type of cell called a cancer-associated fibroblast, which builds protective Cancer vaccines have shown promising results as a means of personalizing cancer immunotherapy and potentially enhancing immune memory in a minority of patients. 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. Despite the exciting potential of immunotherapy, CAF-rich tumours respond poorly to current treatments, resulting in immunotherapy resistance in a large majority of patients. 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. 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. Unfortunately, most patients (around 80%) fail to respond to this type of treatment. But studies have suggested that blocking the activity of checkpoint proteins in exhausted T cells doesn’t achieve that end. 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). “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. ... we reported on RWD on 105 patients on the onset of FT during their immunotherapy treatments. This helps us improve how our site works and ensures we offer you the best content. Until now, treatments that target CAFs as part of cancer therapy have been unsuccessful. Some effector T cells eventually develop, or differentiate, into memory T cells, which can permanently linger in the body … Can Some Women Treated for Endometrial Cancer Forgo Radiation after Surgery? “Our findings in multiple preclinical models of immunotherapy-resistant cancers, including melanoma and breast tumors, show that this novel combination increases the infiltration of tumor-killing T cells, triggers rapid regression of both primary and distant tumors and renders even tumors with poor T-cell penetration responsive to anti-PD-L1 immunotherapy,” says Dr. Ito. 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. 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. Those changes altered the accessibility of chromatin to transcription factors and other components of the transcription machinery. CAFs protect tumours from attack by the immune system by triggering the development of a defensive shield around the tumour. January 16. But once the infection became more chronic, TOX levels spiked and remained high. (117). The Nurse View: Overcoming Challenges Associated with Cancer Immunotherapy. In tumours containing CAF, CD8+ T-cells accumulated at the edge of the tumour mass; this exclusion effect resulted in resistance to anti-tumour vaccination and checkpoint therapy. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. 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. 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. 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. Exhaustion happens “for a reason,” Dr. Schietinger said in a news release, “to prevent the [T] cells from getting overstimulated and dying.”. 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. Would you like to learn more about our services? 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. T cells don’t come in only one flavor. “That’s a strong demonstration of how [removing] a different transcription factor can do almost exactly the same thing,” she said.Â. 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. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Overcoming Cancer’s Financial Toxicity with Real-World Data. 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. 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. Below you can select how you’d like us to interact with you and we’ll keep you updated with our latest content. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Lung cancer is considered to cause the most cancer‐related deaths worldwide. Cancer Immunology: Bench to Bedside Immunotherapy of Cancers will be of special value to clinical immunologists, hematologists, and oncologists. Professor Gareth Thomas of the University of Southampton leads a research team focusing on a particular type of cell called cancer-associated fibroblasts (CAFs). 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. 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