The SREBP Pathway is a Mechanism by which Cancers Subvert Regulatory T Cells

Cancers subvert the immune system in a variety of ways, such as in order to aid growth, or suppress the immune response normally triggered by the presence of cancerous cells. Regulatory T cells are involved in halting the immune response after it is has done its job, and in preventing autoimmunity, in which the immune system attacks the body. This role is abused in cancerous tissue in order to protect the cancer from the immune system. Researchers here identify some of the controlling biochemistry that makes regulatory T cells behave differently in this scenario. The mechanism appears distinct enough, operating only in cancerous tissue, to be a good basis for the development of therapies that could in principle strip much of this protection from a cancer.

Immunologists have discovered that tumors use a unique mechanism to switch on regulatory T cells to protect themselves from attack by the immune system. Surprisingly, the mechanism does not affect regulatory T cell function outside the tumor and may therefore limit the immune-associated toxicities of targeting regulatory T cells. The finding offers the promise of drug treatment to selectively shut down regulatory T cells in a tumor, rendering the tumor vulnerable to cancer immunotherapies that activate the immune system to kill the tumor. The researchers showed that blocking tumor-associated regulatory T cell activity eliminated tumors cells in mice and sensitized the cells to cancer immunotherapy called anti-PD-1 therapy.

Researchers discovered the pathway by challenging mice with melanoma cells and then analyzing which genes were switched on in regulatory T cells. Investigators compared tumor-infiltrating regulatory T cells with regulatory T cells in other tissues to compare gene activation. The experiment revealed a master genetic switch that was activated only in regulatory T cells in the tumor microenvironment. The switch was a transcription factor family called SREBP.

The researchers determined that the tumor-specific regulatory T cell pathway was switched on in a range of cancers - melanoma, breast cancer, and head and neck cancer. The tumor-specific pathway was not switched on in animal models of inflammation or autoimmune disease. Genetically blocking the SREBP pathway selectively in regulatory T cells led to rapid clearance of tumor cells in mice with melanoma and colon adenocarcinoma. Targeting the pathway also reduced tumor growth in mice with established tumors. Blocking the pathway had no effect on the proliferation of regulatory T cells or their overall function in the body.



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