Succinate-SUCNR1 signaling drives Treg-mediated suppression in the solid tumor 4795

Abstract Description The success of T cell therapies in solid tumors is limited by the immunosuppressive tumor microenvironment (TME). The secretion of metabolites in the TME directs the immune landscape, acting as signaling molecules regulating immune responses and reducing the efficacy of cell therapies. Succinate, a mitochondrial metabolite, accumulates in the solid tumor and is secreted into the TME. Mutations in succinate dehydrogenase (Sdh) occur in a range of solid tumors, leading to further accumulation. Studies revealed that tumor-derived succinate promotes suppressive macrophages via the membrane-bound succinate receptor (SUCNR1); therefore, we hypothesized that succinate acts on other suppressive cells in the TME. We identified that the SUCNR1 is more highly expressed on Tregs than CD4+ non Tregs and CD8+ T cells, and SUCNR1 is increased on tumor-infiltrating (TI) Tregs in human melanoma. In vivo studies revealed that high succinate tumors have high TI-Tregs, and Sdh-deficient tumors selectively enhance Treg expansion. SUCNR1+ TI-Tregs have enhanced Granzyme B and GITR. In vitro studies identify the succinate-SUCNR1 axis mediates expansion and of Tregs with increased IL-10, IL-35 and TGFb, an effect dampened by blocking the SUCNR1. We propose this to be a mechanism Tregs use to adapt in the TME, demonstrating the clinical relevance of metabolites in T cell function, and identifying a molecular regulator of Tregs and a novel therapeutic target for enhancing therapies in solid tumors. Funding Sources NIH R21 CA280643 John C. & Karyl Kay Hughes Foundation Endowed Chair & President’s Award Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)