Abstract B060: Elevated tumor secreted metabolites direct immunosuppression by promoting Treg proliferation in the solid tumor

Abstract 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 interstitial space of the TME. Mutations in the succinate processing gene, succinate dehydrogenase (Sdh), occur in a range of solid tumors, leading to further accumulation and secretion. Studies revealed that tumor-derived succinate promotes suppressive macrophages via activation of the membrane-bound succinate receptor (SUCNR1). Regulatory T cell (Tregs) are a central immunosuppressive component of the TME, and high Treg numbers are associated with reduced anti-tumor responses, reduced efficacy of TCR therapies and poor clinical outcomes. Therefore, there is an imminent clinical need to develop synergistic therapies that specifically target Tregs in the TME to successfully overcome the barriers of infiltration and function of antigen-specific T cells. We hypothesized that succinate drives immunosuppression in the solid tumor by promoting Treg proliferation and function, leading to reduced anti-tumor responses to antigen-specific T cells. Consistent with this hypothesis, 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 tumors. Using the NSG mouse model we screened a range of solid tumors and revealed that high succinate tumors have high TI-Tregs, and the Sdh-deficient tumors selectively enhance Treg expansion. Moreover, SUCNR1+ TI-Tregs have enhanced Granzyme B, a marker of suppression, and GITR, a marker of proliferation. In vitro studies identify the succinate-SUCNR1 axis mediates expansion of Tregs and an enhanced immunosuppressive profile with increased levels of IL-10, IL-35 and TGFb, an effect dampened by blocking the SUCNR1 using a small molecule antagonist. We propose the activation of the SUCNR1 to be a mechanism Tregs use to adapt and proliferate in the TME, demonstrating the clinical relevance of metabolites in anti-tumor immunity and T cell function. Targeting Tregs in the TME is an attractive therapeutic strategy and regulating the prolfieration and function of Tregs has the potential to increase the efficacy of effector T cells, thus improving anti-tumor responses by removing a critical suppressive barrier. Taken together, these findings identify a previously unknown molecular regulator of Tregs, providing a novel therapeutic target for enhancing therapies in solid tumors and laying a framework for innovative translational therapeutic development. Citation Format: Sinéad Kinsella, Erin Kirsche, Ian Thompson-Hernandez, Menna Hailemariam, Lauren E Martin, Yuta Asano, Colton W Smith, Kayla Hopwo, Francesco Mazziotta, Aude G Chapuis. Elevated tumor secreted metabolites direct immunosuppression by promoting Treg proliferation in the solid tumor [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B060.