Pitt's study highlights how immune cells help tumors escape the body's defenses

New research from the University of Pittsburgh's Faculty of Medicine and UPMC's Hillman Cancer Center highlights how tumors utilize body's immune regulators to their advantage. Posted today in Immunology of nature, the results could be used to develop the next generation of immune therapies to fight various cancers.

"While cancer immunotherapy drugs that block cell-surface inhibitory molecules such as PD1 have revolutionized cancer care, only about 20% of patients clean their tumors," said the author Principal, Dario Vignali, Ph.D., Frank Dixon Chair in Cancer Immunology, and is Professor and Vice President of Immunology at the Pitt's School of Medicine. "Our findings uncovered a biological mechanism until then unknown, which reveals new therapeutic approaches aimed at promoting anti-tumor immunity."

Vignali and his team have focused on a group of immune cells called regulatory T cells (Tregs), which help maintain a delicate balance in the immune system. To do this, they tamp down immune responses by keeping the system sensitive enough to detect threats, but not to the point of harming autoimmune – attacking normal cells. To achieve this control, Tregs release small proteins called cytokines that can have different effects on cells.

Previous research, including results from Vignali's lab, had shown that tumors intelligently exploit the Tregs in the microenvironment of the tumor to disable killer T cells and escape the body's immune defenses.

In the present study, early authors Deepali Sawant, Ph.D., a former postdoctoral fellow, and Hiroshi Yano, currently a graduate student in Vignali's laboratory, along with the rest of the team, have attempted to shed light The Tregs deactivated killer T cells with two inhibitory cytokines called interleukin-10 (IL-10) and interleukin-35 (IL-35).

Their first discovery, in tumors in mice and humans, was that Treg populations could produce IL-10 or IL-35 but, surprisingly, not both at the same time. "It was unexpected because we had predicted that the activated Tregs would use all the tools at their disposal to suppress the immune responses.For that, it seems like they have to make the choice to secrete only that." 39; a single inhibitory cytokine, "said Vignali, co-head of the immunology program and immunotherapy against cancer 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 the IL-35.

"It's like making a latte, you need both coffee and milk," Vignali explained. "Without both, you will not have latte!"

In furthering their research, they discovered that cytokines, acting together, activated a protein called BLIMP1, which effectively inhibited killer T-cells by making them express a wide variety of inhibitory cell surface molecules, such as PD1, LAG3, TIM3 and TIGIT, which inhibit their ability to detect and kill cancer cells.

This discovery is important, says Vignali, because many current clinical trials focus on immunotherapies that only block one or two of these inhibitory proteins that, in turn, would activate killer T cells. But developing drugs that block IL-10 or IL-35 could have a much greater effect in preventing the expression of many inhibitory proteins at once.

The authors also note that, since Tregs targeting drugs are already tested in clinical trials, the search for specific mechanisms by their work could provide clues to make the drugs more effective or help design better combinations with them. immunotherapies currently available to improve treatment success.