IDH Mutations Suppress T Cell–Mediated Antitumor Immunity

Mutations in the isozymes isocitrate dehydrogenase 1 (IDH1) and IDH2, which frequently occur in gliomas and have been shown to promote gliomagenesis, result in the reduction of alpha-ketoglutarate (α-KG) to the α-KG analog (R)-2-hydroxyglutarate (R-2-HG). Recently, extratumoral R-2-HG has been detected in the body fluids of patients with IDH-mutant tumors. To ascertain the effects of R-2-HG accumulation on the tumor microenvironment, Bunse, Pusch, Bunse, and colleagues investigated the role of R-2-HG in T-cell–mediated antitumor immunity. T cells cultured with either exogenous R-2-HG or IDH1-mutant glioma cells exhibited increased levels of intracellular R-2-HG via sodium-dependent and organic anion transporter–mediated importation of exogenous R-2-HG. Further, uptake of exogenous R-2-HG reduced the proliferation and effector function of activated T cells; similarly, analysis of patient gliomas showed that intratumoral T cells were present at lower levels and exhibited decreased proliferation in IDH1-mutant gliomas compared to IDH1–wild-type gliomas. Exogenous R-2-HG suppressed extracellular calcium influx and nuclear translocation of NFAT, a calcium-regulated transcription factor that regulates the expression of critical immune response–related genes in T cells. In activated T cells, R-2-HG–mediated inhibition of ATP synthase led to decreased mitochondrial ATP production, resulting in decreased T-cell receptor (TCR) signaling. Moreover, R-2-HG–driven ATP loss increased AMPK phosphorylation induced decreased calcium signaling, which subsequently inhibited NFAT, and repression of polyamine biosynthesis, thus collectively repressing T-cell proliferation and early TCR signaling events. Consistent with these findings, mice bearing Idh1-mutant tumors exhibited reduced levels of tumor-infiltrating lymphocytes (TIL) and antigen-presenting cells compared to mice with Idh1–wild-type tumors, and Idh1 mutant–derived R-2-HG blocked immunotherapy-mediated antitumor immune responses in vivo. Cotreatment with IDH1-mutant inhibitors enhanced the efficacy of immunotherapy against Idh1-mutant tumors in vivo. Together, these results identify and characterize the effects of an oncometabolite on the glioma tumor immune microenvironment and suggest that the tumor-intrinsic and tumor microenvironmental functions of oncometabolites may drive tumorigenesis.

Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nature Med 2018 July 9 [Epub ahead of print].

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