OS10.2 R-2-Hydroxyglutarate shapes the immune microenvironment in IDH1-mutant gliomas

Background : IDH1-mutant tumors form the majority of grade II and grade III gliomas, qualifying as a new entity in the 2016 WHO classification of CNS tumors. We have previously shown that a peptide vaccine encoding the IDH1(R132H) epitope evokes an MHC II-restricted CD4+ T Helper-1 cell (Th1) immune response and is therapeutic in an MHC-humanized A2.DR1 mouse tumor model. Ongoing efforts focus on further unleashing both the innate and adaptive immune system in targeting IDH1(R132H)-mutant gliomas. While the tumor-cell-intrinsic consequences of R-2-hydroxyglutarate (R-2-HG)-production, rendered by the IDH1-mutation, are well characterized, potential paracrine effects influencing antitumor immunity remain enigmatic. However, they are important to decipher, as immunotherapies targeting IDH1-mutant gliomas are emerging. Aim : This study aimed at characterizing a potential cell-specific modulatory role of the oncometabolite R-2-HG in shaping the immune microenvironment of IDH1-mutant gliomas. Methods and results : By means of expression dataset analyses, syngeneic murine tumor models and human glioma tissue, as well as a novel astrocyte-specific IDH1R132H-knock in model, we demonstrate that R-2-HG impairs endogenous and IDH1(R132H)-specific antitumor T cell immunity. This is underlined by functional and transcriptomic analyses of myeloid cells indicating a R-2-HG-driven induction of tolerogenicity and compromised antigen presentation. Metabolomic profiling was complemented by mitochondrial respiration assays, calcium measurements and pathway analyses in primary human and mouse immune cells to delineate key molecular mechanisms by which tumor-derived R-2-HG corrupts the glioma immunoenvironment. The functional relevance of R-2-HG-mediated impairment of antitumor immunity was demonstrated in vivo and potential pharmacological strategies abrogating its effects were assessed. Conclusion : Glioma-derived R-2-HG impairs antitumor immunity by affecting both infiltrating T-cells and the associated myeloid compartment, thus contributing to tumorigenesis and resistance to therapy. Immunotherapeutic strategies against IDH-mutant gliomas may benefit from approaches to prevent excess R-2-HG production or its uptake by immune cells.