Tumor Immune Evasion Through STING-Mediated T Cell Death
The interaction between tumor cells and T cells dictates antitumor immune response. While T cells recognize tumor cells and secrete cytotoxic cytokines for tumor killing, tumor cells also develop strategies to evade T cell immunity control. Understanding the mechanism of tumor immune evasion of T cell killing is critical for the development of more efficacious cancer immunotherapies. STING is a crucial innate immune sensor that plays a central role in antitumor immunity. STING senses cGAMP in the tumor microenvironment (TME) and primes antigen presentation to activate T cell antitumor immunity. However, we found that T cells are extremely sensitive to cGAMP-mediated cell death in TME. Sting-deficient T cells are tolerant to tumor-derived cGAMP killing thus resulting in better tumor control compared to WT T cells. The tumor cell-T cell interaction is mediated by an immunotransmitter cGAMP which is secreted by tumor cells, and then taken up by the surrounding T cells to induce STING-mediated cell death. The overall goal of this project is to understand the molecular mechanisms by which tumor cells trigger STING-mediated T cell death, and to develop strategies to block this pathway to improve cancer immunotherapy. Aim 1 will elucidate the molecular mechanism of cGAMP import and signaling cascade of STING-mediated cell death in T cells. Aim 2 will develop novel combinational therapy through blockade of STING-mediated T cell death. Studies proposed here will elucidate a new mechanism of tumor immune evasion through cGAMP-mediated T cell death, which may have a tremendous therapeutic value.