Cancers thrive and spread in part because of their ability to create fortresses around themselves that ward off the body’s natural immune defenses, a so-called immunosuppressive microenvironment.
Although a healthy body’s defenses against cancer and infection are driven by T cells that recognize and destroy foreign intruders, the environment created by cancer tumors often prevents this system from working. A new City of Hope study may ultimately provide a way to overcome this challenge to T cells.
City of Hope scientists had long established that the protein STAT3 regulates a large array of genes in tumor cells, including those related to immunosuppression. Their new study, published this month in the journal Cell Reports, sheds light on how STAT3 interacts with another key protein, known as S1PR1, to regulate T cells that suppress the immune system. Those T cells are known as regulatory T cells, or Tregs.
“This has many therapeutic implications,” said Saul Priceman, Ph.D., an assistant research professor at City of Hope and the study’s first author. “This could be helpful across the board for solid cancers in combination with other immunotherapies. In most solid cancers, these proteins are blocking the immune system from killing the tumor. Our new findings suggest that by selectively targeting S1PR1, we can put the brakes on T cells that prevent the immune system from effectively attacking the tumor.”
Efforts to target STAT3 with medications have been unsuccessful because the protein lacks the enzymatic activity that would allow drugs to bind to it. In healthy people, the STAT3 protein is activated to fight infections or inflammation. One of the first normal actions of the protein is to touch off a gene that will eventually shut the protein down once it’s done its job. But in cancer cells, that “shut-off” mechanism is not induced. The activated protein propagates, and becomes a useful tool for the cancer to block the body’s immune system and promote cancer progression.
City of Hope scientists identified S1PR1 as a crucial molecule that activates STAT3 and promotes the accumulation of T cells that suppress the immune system, effectively protecting the tumors from the body’s natural defenses. By targeting S1PR1 or STAT3 , either using drugs or genetic models, Priceman and his colleagues were able to block these T cells and inhibit tumor growth.
Another study in the group’s arsenal, which it plans to soon publish, describes a novel therapeutic platform that selectively targets these immunosuppressive or defective T cells, including Tregs, leading to a shut down of STAT3 activity. The combined findings of these studies will eventually lead to more powerful therapies to combat evasion of anti-tumor immunity.