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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 6

Decreased STAT1 positive cells in IDH-MUT compared with IDH-WT LGG tumor sections.

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Decreased STAT1 positive cells in IDH-MUT compared with IDH-WT LGG tumor...
(A) Representative images showing STAT1 staining on IDH-WT and IDH-MUT WHO grade III LGG samples. Scale bars: 80 μm and 8 μm. (B) Quantification of STAT1+ cells per area of tumor (mm2) on IDH-WT (56 sections from 9 cases) and IDH-MUT (23 sections from 11 cases) tumors. Data represent the mean ± SD. Data obtained by 2-tailed unpaired t test. (C) RT-PCR analysis of Stat1, Cxcl9, and Cxcl10 expression in GL261WT cells stimulated with 10 ng/ml recombinant murine IFN-γ for 12 hours, 36 hours after transfection with 1 μg plasmid encoding either scrambled shRNA (OriGene Technologies; TR30013) or 4 shRNAs targeting STAT1 (OriGene Technologies; TG502153). (D) CXCL10 ELISA was performed using supernatant from the cells described in C. Data shown in C and D represent the mean ± SD of 3 biologic replicate samples and are representative of 2 independent experiments; ***P < 0.0001. sh-Ctrl, sh-control.
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