Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas
Gary Kohanbash ... Joseph F. Costello, Hideho Okada
Gary Kohanbash ... Joseph F. Costello, Hideho Okada
Published April 3, 2017
Citation Information: J Clin Invest. 2017;127(4):1425-1437. doi:10.1172/JCI90644.
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Categories: Research Article Immunology Oncology

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

Abstract

Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte–associated genes and IFN-γ–inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors. Given these findings, we have investigated the impact of IDH mutations on the immunological milieu in LGG. In immortalized normal human astrocytes (NHAs) and syngeneic mouse glioma models, the introduction of mutant IDH1 or treatment with 2HG reduced levels of CXCL10, which was associated with decreased production of STAT1, a regulator of CXCL10. Expression of mutant IDH1 also suppressed the accumulation of T cells in tumor sites. Reductions in CXCL10 and T cell accumulation were reversed by IDH-C35, a specific inhibitor of mutant IDH1. Furthermore, IDH-C35 enhanced the efficacy of vaccine immunotherapy in mice bearing IDH-MUT gliomas. Our findings demonstrate a mechanism of immune evasion in IDH-MUT gliomas and suggest that specific inhibitors of mutant IDH may improve the efficacy of immunotherapy in patients with IDH-MUT gliomas.

Authors

Gary Kohanbash, Diego A. Carrera, Shruti Shrivastav, Brian J. Ahn, Naznin Jahan, Tali Mazor, Zinal S. Chheda, Kira M. Downey, Payal B. Watchmaker, Casey Beppler, Rolf Warta, Nduka A. Amankulor, Christel Herold-Mende, Joseph F. Costello, Hideho Okada

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Syngeneic IDH-MUT murine gliomas demonstrate reduced chemokine- and IFN-...

Figure 3

Syngeneic IDH-MUT murine gliomas demonstrate reduced chemokine- and IFN-γ pathway–related genes and CTL infiltration.

C57BL/6 mice received intracranial injections of 1 × 105 GL261 or SB28 glioma cells stably transfected with cDNA for either WT or the R132H form of IDH1. Day-21 tumors were removed from mice and further assessed. (A) RT-PCR analysis of SB28 tumor–derived RNA showing decreased expression of CTL response–related genes in SB28-MUT (MUT tumor; n = 4) versus SB28-WT (WT tumor; n = 4) tumors. (B) CXCL10 ELISA was performed on tumor-derived protein extracts from mice bearing GL261-WT or GL261-MUT tumors. (C) Representative fluorescence microscopy images from sections stained with DAPI (blue), CD3 (magenta), and CD8 (yellow) on frozen tumor sections from mice bearing GL261-WT or GL261-MUT tumors. Cells were imaged as described in Figure 2. Scale bars: 10 μm. (D) Quantification of CD3+CD8+ dp cells from GL261-WT (n = 14) and GL261-MUT (n = 16) tumors using StrataQuest software. P values were obtained using a 2-sided, unpaired t test.