New research from the University of Pittsburgh School of Medicine and the UPMC Hillman Cancer Center sheds light on how tumors use the body’s regulators of immunity for their own benefit. Published in Nature Immunology, the findings could be used to develop the next generation of immune therapies to fight various cancers. McGowan Institute for Regenerative Medicine affiliated faculty member James Luketich, MD—Henry T. Bahnson Professor of Cardiothoracic Surgery, the Chairman, Department of Cardiothoracic Surgery, the Chief, Division of Thoracic and Foregut Surgery, the Director, Thoracic Surgical Oncology, the Co-Director, Lung Cancer Center, the Associate Director of Surgical Affairs, University of Pittsburgh Cancer Institute, and the Director, Mark Ravitch/Leon C. Hirsh Center for Minimally Invasive Surgery—is a co-author on the paper.
“While cancer immunotherapy drugs that block inhibitory cell surface molecules like PD1 have revolutionized cancer care, only about 20 percent of patients clear their tumors,” said senior author Dario Vignali, PhD, who holds the Frank Dixon Chair in Cancer Immunology, and is professor and vice chair of immunology at Pitt’s School of Medicine. “Our findings uncovered a previously unknown biological mechanism that reveals new therapeutic approaches to promote anti-tumor immunity.”
Dr. Vignali and his team focused on a group of immune cells called regulatory T cells (Tregs), which help maintain a delicate balance in the immune system. They do so by tamping down immune responses, keeping the system sensitive enough to catch threats, but not so sensitive that they result in autoimmunity – attacking normal cells. To achieve this control, Tregs release small proteins called cytokines that can have different effects on cells.
Previous research, including findings from Dr. Vignali’s lab, had shown that tumors cleverly take advantage of Tregs inside the tumor’s microenvironment to turn off killer T cells and evade the body’s immune defenses.
In the current study, first authors Deepali Sawant, PhD, a former post-doctoral fellow, and Hiroshi Yano, a current graduate student in Dr. Vignali’s lab, along with the rest of the team, set about trying to shed light on how Tregs turned off killer T cells using two inhibitory cytokines called interleukin-10 (IL-10) and interleukin-35 (IL-35).
Their first finding, in mouse and human tumors, was that populations of Tregs could either make IL-10 or IL-35 but, surprisingly, not both at the same time. “This was unexpected because we had anticipated that activated Tregs would use all tools available to them to suppress immune responses. Instead it seems they have to make a choice to secrete only one inhibitory cytokine,” noted Dr. Vignali, who also is co-leader of the Cancer Immunology and Immunotherapy Program at the UPMC Hillman Cancer Center.
The team then used a mouse model of cancer to show that for tumors to effectively suppress the immune system, they needed both types of Treg cells – those that secrete IL-10 and those that secrete IL-35.
“It’s like making a latte; you need both coffee and milk,” explained Vignali. “Without both, you won’t have a latte!”
Investigating further, they found that the cytokines, acting together, activated a protein called BLIMP1, which effectively disabled killer T cells by making them express a large variety of inhibitory cell surface molecules, such as PD1, LAG3, TIM3 and TIGIT, which suppresses their ability to detect and kill cancer cells.
This finding is important, says Dr. Vignali, because many current clinical trials are focused on immunotherapies that block just one or two such inhibitory proteins that would, in turn, activate killer T cells. But developing drugs that block IL-10 or IL-35 could have a much greater effect by preventing the expression of many inhibitory proteins at once.
The authors also note that since drugs targeting Tregs are already being tested in clinical trials, finding the precise mechanisms by which they work could provide clues to making more effective drugs, or help design better combinations with currently available immunotherapies to improve treatment success.
The study was funded by National Institutes of Health grants R01 CA203689, P01 AI108545, P30 CA047904 and S10 OD011925, and by Tizona Therapeutics. Dr. Vignali and study co-author Creg Workman, PhD, of Pitt, have submitted patents covering IL-35.
Illustration: UPMC/Hillman Cancer Center.
Abstract (Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Deepali V. Sawant, Hiroshi Yano, Maria Chikina, Qianxia Zhang, Mengting Liao, Chang Liu, Derrick J. Callahan, Zhe Sun, Tao Sun, Tracy Tabib, Arjun Pennathur, David B. Corry, James D. Luketich, Robert Lafyatis, Wei Chen, Amanda C. Poholek, Tullia C. Bruno, Creg J. Workman & Dario A. A. Vignali. Nature Immunology; online April 1, 2019.