D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells

Purpose: Somatic mutations in the isocitrate dehydrogenase (IDH)-1 and -2 genes are remarkably penetrant in diffuse gliomas. These highly effective gain-of-function mutations enable mutant IDH to efficiently metabolize isocitrate to D-2-hydroxyglutarate (D 2-HG) that accumulates to high concentrations within the tumor microenvironment.D2-HG is an intracellular effector that promotes tumor growth through widespread epigenetic changes in IDH-mutant tumor cells, but its potential role as an intercellular immune regulator remains understudied. Experimental Design: Complement activation and CD4 ⁺, CD8 ⁺, or FOXP3 ⁺ T-cell infiltration into primary tumor tissue were determined by immunohistochemistry using sections from 72 gliomas of World Health Organization (WHO) grade III and IV with or without IDH mutations. Ex vivo experiments with D 2-HG identified immune inhibitory mechanisms. Results: IDHmutation associated with significantly reduced complement activation and decreased numbers of tumorinfiltrating CD4 ⁺ and CD8 ⁺ T cells with comparable FOXP3 ⁺/ CD4 ⁺ ratios. D 2-HG potently inhibited activation of complement by the classical and alternative pathways, attenuated complement-mediated glioma cell damage, decreased cellular C3b(iC3b) opsonization, and impaired complement-mediated phagocytosis. Although D2-HG did not affect dendritic cell differentiation or function, it significantly inhibited activated T-cell migration, proliferation, and cytokine secretion. Conclusions: D 2-HG suppresses the host immune system, potentially promoting immune escape of IDH-mutant tumors.