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

Abstract

<b>Purpose:</b> 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. D 2-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.<b>Experimental Design:</b> 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. <i>Ex vivo</i> experiments with D 2-HG identified immune inhibitory mechanisms.<b>Results:</b> IDH mutation associated with significantly reduced complement activation and decreased numbers of tumor-infiltrating 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 D 2-HG did not affect dendritic cell differentiation or function, it significantly inhibited activated T-cell migration, proliferation, and cytokine secretion.<b>Conclusions:</b> D 2-HG suppresses the host immune system, potentially promoting immune escape of IDH-mutant tumors. <i>Clin Cancer Res; 24(21); 5381-91. ©2018 AACR</i>.