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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 1

Reduced CD8+ T cell numbers in WHO grade III IDH-MUT gliomas compared with IDH-WT gliomas.

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Reduced CD8+ T cell numbers in WHO grade III IDH-MUT gliomas compared wi...
FFPE sections from IDH-WT (n = 9) and IDH-MUT (n = 11) WHO grade III gliomas were stained for CD3 (Cy5) and CD8 (Texas Red [TEX]) and analyzed using StrataQuest software. (A) Representative staining for CD3 (red), CD8 (yellow), and nuclei (blue) either alone or merged in both IDH-WT (WT) and IDH-MUT (MUT) cases. Red circles represent automated cell masks on CD3 and CD8 dp cells. Scale bars: 20 μm. (B) Number of CD3+CD8+ dp cells per area (mm2) of tumor calculated for each case. The average tumor area per tissue section was 111.21 mm2 for IDH-WT and 165.35 mm2 for IDH-MUT cases. (C) Scatter diagrams illustrating the staining intensity of CD3 and CD8 on the x and y axes, respectively. The percentage of cells in each quadrant was based on the total number of DAPI+ (blue) nuclei. Each dot represents an individual case. (D) CD3+CD8+ dp cells as a percentage of total DAPI+ cells (nuclei) calculated for each case. In B and D, each dot represents a value from a single patient, black lines represent the mean, and error bars indicate the SD of samples in a group. P values were obtained using a 2-sided, unpaired Mann-Whitney U test.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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