Deciphering the Roles of STING-Mediated T cell Pyroptosis in Antitumor Immunity

PROJECT SUMMARY An immunosuppressive tumor microenvironment presents a significant hurdle in controlling tumor growth. Activation of the stimulator of interferon genes (STING) protein initiates innate immune responses, potentially overcoming tumor immunosuppression and eliciting potent antitumor immune responses. However, in clinical

trials, STING agonist therapy has encountered profound tumor resistance, and the mechanisms remain unclear. There is a significant gap in our understanding of the negative regulatory effects of STING on antitumor immunity that underlies resistance development in STING agonist therapy. STING is a crucial innate immune sensor that

senses 2’3’-Cyclic GMP-AMP (cGAMP) produced by Cyclic GMP-AMP synthase (cGAS) to activate interferon (IFN) signaling. Within the complex tumor microenvironment (TME), extracellular cGAMP can be imported into various cell types, including myeloid cells, Natural Killer (NK) cells, and fibroblasts, inducing STING-mediated

IFN signaling and eliciting potent antitumor immune responses. However, our research has demonstrated that cGAMP importation into tumor-infiltrating T cells (TILs) can adversely induce STING-mediated cell death of the T cells, and that this is an important mechanism by which tumors evade immune destruction in mouse tumor

models. Thus, STING activation in the TME both positively and negatively regulates antitumor immunity. These results lead us to propose the hypothesis that tumors evade T cell mediated immune surveillance through cGAMP importation into tumor-infiltrating T cells that induces a STING-mediated cell death pathway

independently of IFN. The objective of this project is to elucidate the mechanisms of cGAMP-STING-mediated T cell death, and to develop strategies for blocking STING-mediated T cell death. Given that STING agonists are now in development for use as cancer therapeutics, directing activation of STING-mediated IFN signaling

while avoiding STING-mediated death of TILs will improve the success of STING agonist therapy. Aim 1 will identify cGAMP importers and IFN-induced mediators facilitating cGAMP importation into T cells. Aim 2 will elucidate the molecular mechanisms underlying cooperative activation of STING with TCR signaling in triggering

T cell pyroptosis. Aim 3 will develop novel immunotherapies via blockade of STING-mediated T cell death. The proposed studies here will elucidate a novel mechanism by which cGAMP is imported into tumor-infiltrating T cells to activate STING-mediated cell pyroptosis. We anticipate that the insights gained from our studies will

have a significant impact on STING-based cancer immunotherapies.