PITTSBURGH, Dec. 21, 2022 — When T cells, the immune system’s main anti-cancer agents, work overtime to fight a tumor, they can enter a state of exhaustion where they no longer function properly. in a new nature immunology In a study, researchers from the University of Pittsburgh and the UPMC Hillman Cancer Center report that the low-oxygen environment of tumors can cause these tired T cells to switch allegiance so that they suppress the immune system instead of fighting cancer. .
“We often think of our immune system in absolute terms: certain types of cells are ‘good,’ and some are ‘bad,'” said lead author Greg Delgoffe, Ph.D., an associate professor of immunology at Pitt’s medicine School and director of the Tumor Microenvironment Center in UPMC Hillman Cancer Center. “The key takeaway from our work is that our immune system is critically sensitive to its local environment. In the right environment, cells that are normally thought to be anti-cancer can switch sides and work against us.”
The new study, led by Paolo Vignali, Ph.D., a student in Pitt’s Medical Scientist Training Program, also showed that focusing on low oxygen levels reduced the suppressive nature of depleted T cells and enhanced the response to immunotherapy.
Delgoffe and Vignali elaborated on the study findings and how they might inform next steps in therapy development.
What are depleted T cells and what role do they play in cancer and other diseases?
GD: Depleted T cells are the soldiers of our immune system that have been waging their battle against cancer constantly and relentlessly. Our immune system uses T cells to find and kill abnormal cells, such as those that are cancerous or infected with a virus, and they are designed to keep fighting until each abnormal cell is killed. But in diseases like cancer, where cancer cells keep up with the immune system, the T cells can fail in their job and the abnormal cells remain. As the T cells continue to fight these cancer cells, their job gets worse and worse.
VP: Exhausted T cells are an adaptive response to too much “signal”. These signals can come from pathological sources, such as cancer or a virus, but they also arise in healthy tissue, which is why we find depleted T cells in autoimmune diseases, where the immune system attacks the host inappropriately, and in the placenta where the mother’s immune system adapts to the growing fetus. In these settings, T cell depletion is a good thing: it helps control unwanted damage by activated T cells.
What did you learn about depleted T cells in this new study?
GD: As depleted T cells no longer do their job of killing cancer cells well, they have become targets for cancer immune therapies. The idea is that if we can reinvigorate them, they will go back to killing cancer cells effectively. What we learned in our study is that when depleted T cells enter tumors, they not only become less functional; they actually change the environment around them to actively shut down other nearby cells. In other words, depleted T cells not only don’t work for us; they are actively working against us.
VP: The idea that depleted T cells are working against us in cancer opens up new avenues for immunotherapy, such as developing treatments to attack the pathway responsible for side-switching or engineering better T cells for cell-based therapies. While the field of immunotherapy has legitimately focused on correcting the loss of anti-cancer functions of T cells, our efforts show that we should also be looking into possible new behaviors acquired by these cells.
Did any of the results surprise you?
GD: Depleted T cells have many similarities to regulatory T cells, a type of T cell that helps the immune system control itself to prevent autoimmune diseases. We found that depleted T cells functionally mimic regulatory T cells by suppressing the immune system. We had some clues about this find, so it wasn’t too surprising. However, we were surprised to find that the immunosuppressive function of depleted T cells was linked to the environment in which we studied them. In summary, we found that the more aggressive tumors tended to have more depleted immunosuppressive T cells, while the slower growing tumors had depleted T cells that were simply less functional, but not suppressive.
What do their findings suggest about targeted therapies for depleted T cells?
GD: The observation that the local tumor environment dictated whether or not depleted T cells were immunosuppressive was a clue. He told us that if we could reprogram or modulate the local environment, perhaps the repressive nature of these cells could be reversed. And that turned out to be the case: We use drugs that don’t specifically target T cells, but instead change the battlefield they’re fighting on by attacking the tumor’s vasculature and metabolism. We found that making conditions more favorable was enough to deplete T cells within these treated tumors to moderate those anti-inflammatory functions, thereby enhancing tumor response to various immune-based cancer therapies.
VP: The finding that we could reverse anti-inflammatory functions in depleted T cells is particularly exciting. Many large and sophisticated studies have taught us that most of the characteristics of depleted T cells are irreversible: they are stuck being poor tumor killers. However, the battle between the immune system and cancer is a delicate balancing act. Here, our data shows that we can take aim at the battlefield and shift the balance in favor of immune cells, even in large, aggressive tumors.
What are the next steps for this research?
GD: We are currently conducting several clinical trials in Pittsburgh using these environmental modulating drugs in cancer patients. The next big question will be whether we can reverse the immunosuppressive character of depleted T cells in these patients. We are also interested in developing drugs that directly target the suppressive nature of T cells in patients. Beyond cancer, depleted T cells also show up in chronic infections like hepatitis and HIV, autoimmune diseases like lupus and type 1 diabetes, and in the gut. Discovering the role of these cells and their suppressive character in other contexts will be a new direction for this research.
Other contributing authors to the study included Kristin DePeaux, BS, McLane Watson, Ph.D., Chenxian Ye, MS, Rhodes Ford, BS, Konstantinos Lontos, MD, Nicole McGaa, Nicole Scharping, Ph.D., Ashley Menk, MS , Amanda Poholek, Ph.D., and Dayana Rivadeneira, Ph.D., all of Pitt or UPMC; and Simon Robson, Ph.D., of Harvard Medical School.
This research was supported by the National Institutes of Health (NIH; DP2AI136598, T32CA082084, F30CA247034, F31AI149971, and F31CA247129), Hillman Fellows for Innovative Cancer Research Program, Stand Up to Cancer, and the American Association for Cancer Research (SU2C-AACR- IRG -04-16), Alliance for Cancer Gene Therapy, UPMC Hillman Cancer Center Skin Cancer and Head and Neck Cancer SPORE (P50CA121973 and P50CA097190), Mark Foundation for Cancer Research, Cancer Research Institute, Sy Holzer Endowed Immunotherapy Fund and the Nucleus of Health Sciences Sequencing at UPMC Children’s Research Hospital of Pittsburgh and the Center for Research Informatics at the University of Pittsburgh. This research also used the flow cytometry and animal facilities of the UPMC Hillman Cancer Center, supported in part by the NIH (P30CA047904).
About the University of Pittsburgh Schools of Health Sciences
The University of Pittsburgh Schools of Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health Sciences and Rehabilitation, and Public Health. The schools serve as academic partners of the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow’s healthcare specialists and biomedical scientists, participate in innovative research that will advance the understanding of the causes and treatments of disease, and participate in the delivery of exceptional patient care. Since 1998, Pitt and its affiliated university faculty have been ranked among the top 10 educational institutions in support of grants from the National Institutes of Health. For additional information on the Faculties of Health Sciences, visit www.health.pitt.edu.
About UPMC Hillman Cancer Center
UPMC Hillman Cancer Center connects patients with the integrated expertise of leading physicians, academic researchers, specialty programs, and treatment centers. By partnering with the University of Pittsburgh School of Medicine, the UPMC Hillman Cancer Center, the only National Cancer Institute-designated Comprehensive Cancer Center in the region, is accelerating advancements from laboratory to clinical practice around the world. UPMC – ranked nationally by US news and world report for excellence in cancer care: has more than 70 cancer treatment centers in Pennsylvania, Ohio, New York and Maryland, as well as centers in Ireland and Italy. Backed by the collective strength of UPMC, UPMC Hillman Cancer Center offers cutting-edge treatments and the latest clinical research to transform cancer research, care and prevention, one patient at a time.
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