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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 March 20, 2017
Citation Information: J Clin Invest. 2017;127(4):1425-1437. https://doi.org/10.1172/JCI90644.
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Research Article Immunology Oncology

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

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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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Figure 2

Lower expression levels of CD8+ T cell–associated genes in IDH-MUT versus IDH-WT patients.

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Lower expression levels of CD8+ T cell–associated genes in IDH-MUT versu...
TCGA level 3 gene expression data were downloaded from the University of California Santa Cruz Cancer Genome Browser for 1p/19q intact, WHO grade II or III glioma cases (n = 207) (http://www.cbioportal.org/). IDH-MUT (n = 149) and IDH-WT (n = 58) cases were compared for immune cell and immune effector gene expression levels. Differentially expressed genes associated with (A) CD8+ CTLs and (B) IFNG and IFN-γ–inducible genes. (C) Gene expression associated with immunosuppression (TGFB1), CD4 T cells (CD4), and type 2 immunity (IL5 and IL10). Graphs depict the log2 expression value of each gene: each dot represents 1 patient; black bars show the average value. P values were determined using 2-sided, unpaired t tests, with Benjamini-Hochberg adjustment for multiple testing.
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