How do immune cells help tumors escape the body's defenses?

In recent years, the fourth largest therapy for cancer, immunotherapy, has brought new breakthroughs in cancer treatment. Although immunotherapeutic drugs that block inhibitory cell surface molecules such as PD1 have revolutionized cancer treatment, only a small percentage of specific patients benefit from this therapy. Therefore, the problem that needs to be solved urgently is still to find out how the tumor escapes the defense of the body or the surveillance of the immune system.

A new study led by the University of Pittsburgh School of Medicine and the UPMC Hillman Cancer Center illustrated a new biological mechanism that uncovers new treatments that promote anti-tumor immunity. The findings, published in the journal Nature Immunity, can be used to develop next-generation immunotherapies to combat a variety of cancers.

The research team focused on a group of immune cells called regulatory T cells (Tregs) that help maintain the delicate balance of the immune system. By releasing a small protein called a cytokine, Tregs keeps the immune system sensitive enough to capture the threat of foreign substances without causing autoimmunity to attack normal cells. Cytokines can have different effects on cells.

Previous studies have shown that tumors cleverly use Tregs in the tumor microenvironment to shut down killer T cells and evade the body's immune defenses. Moreover, the proportion of Tregs cells in the peripheral blood of various cancer patients is elevated, which also indicates the patient's survival and poor prognosis of treatment.

The researchers began trying to figure out how Tregs shut down killer T cells using two inhibitory cytokines called IL-10 (interleukin-10) and IL-35 (interleukin-35).

In mouse and human tumors, they first discovered that the Tregs population could produce IL-10 or IL-35, but surprisingly they could not produce IL-10 or IL-35 at the same time. Unlike the expected results that activated Tregs will use all the tools they have available to suppress the immune response, they seem to have to choose to secrete only one inhibitory cytokine.

The team then used a mouse cancer model to show that the tumor effectively represses the immune system, and they need two types of Treg cells that secrete IL-10 and IL-35 cells, respectively.

Further research, they found that cytokine interaction activates a protein called BLIMP1, which effectively inhibits the ability of killer T cells to detect and kill cancer cells by making killers T cells express a variety of inhibitory cell surface molecules, such as PD1, LAG3, TIM3, and TIGIT.

This finding is important because many current clinical trials focus on immunotherapy, which blocks only one or two such inhibitory proteins. And these inhibitory proteins, in turn, activate killer T cells. However, the development of drugs that block IL-10 or IL-35 can produce greater effects by simultaneously preventing the expression of many inhibitory proteins.

Since drugs for Tregs have been tested in clinical trials, finding the precise mechanism by which they work can provide clues to making more effective drugs, or help design better combinations with existing immunotherapies to improve treatment success rates.