STING agonist enhances type I interferon-driven GITRL co-stimulatory functions in monocytic lineage cells for durable and effective anti-tumor CD8+ T cell responses 3684

Abstract Description Opimizing T cell-based therapies requires mechanistic insights into T cell activation, which involves Ag/MHC (signal 1), co-stimulation (signal 2), and cytokinessuch as type I interferons (IFN-I) (signal 3). Our group previously showed that the co-stimulatory receptor GITR provides a post-priming survival signal, “signal 4,” enhancing T cell accumulation during viral infections. GITR ligand (GITRL), mainly induced on inflammatory monocytic lineage cells (infMC) by IFN-I, is not well-studied in tumors where IFN-I arises from the cGAS-STING pathway. To examine GITRL-mediated signal 4 in cancer, we used a STING agonist to induce IFN-I via the cGAS-STING pathway. Treatment with one dose of STING agonist was used to examine the rapidly induced GITRL signaling on effector T cells, while three doses were used to study its impact on tissue resident memory T cell (TRM). STING agonist treatment resulted in IFN-I-dependent GITRL upregulation on infMCs in tumors. We also showed that conditional deletion of GITRL on CCR2+ infMCs impairs STING agonist-induced tumor control. Using GITR+/+: GITR-/- mixed bone marrow chimeras, we showed that GITR+/+ CD8+ T cells outcompete GITR-/- counterpart upon STING agonist treatment. Similarly, we found that GITR+/+ CD8+ skin TRM forms locally and have a competitive advantage over GITR-/- counterpart. Together, these data showed that STING agonist promotes GITR/GITRL co-stimulation, enhancing effector and TRM accumulation for improve tumor control. Funding Sources This research was funded by Canadian Cancer Society grant #706759, Canadian Institutes of Health Research grants # FDN-143250, PJ4-185649 and PJT 190128 (all to THW) and a CHIR Canada graduate scholarships doctoral award (MG). THW holds the Canada research chair in anti-viral immunity at the University of Toronto Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)