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.
View: Text | PDF
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

×

Figure 7

Treatment with IDH-C35 improves the efficacy of peptide vaccines in mice bearing GL261-MUT tumors.

Options: View larger image (or click on image) Download as PowerPoint
Treatment with IDH-C35 improves the efficacy of peptide vaccines in mice...
C57BL/6 mice were vaccinated 3 times with synthetic peptides encoding GAAs presented by GL261 cells (EPHA2671–679, EPHA2682–689, TRP2180–188, GARC1177–185, and HBV core128–140) emulsified in IFA with 20 μg poly-ICLC as an adjuvant. Control mock vaccines consisted of 100 μg HBV core128–140, but without GAA peptides emulsified in IFA with 20 μg Poly-ICLC. Vaccinated mice received intracranial injections of either 1 × 105 GL261-WT or 1 × 105 GL261-MUT cells and received daily treatment with vehicle or 450 mg/kg/day IDH-C35. (A) Kaplan-Meier curves demonstrating survival of mice bearing GL261-WT or GL261-MUT gliomas in the brain (n = 10/group). (B and C) Mice that received treatments and intracranial tumor challenge as above were sacrificed on day 21 after tumor inoculation for evaluation of immune responses. Data are representative of 2 independent experiments with similar results. (B) Representative flow cytometric analysis of tumor-infiltrating CD3+CD8+ T cells gated on CD45+ live lymphocytes. Q3, gating on CD45+ live lymphocytes; UL, upper left; UR, upper right; LL, lower left; LR, lower right. (C) Mean percentage of tumor-infiltrating CD3+CD8+ cells from each treatment group (n = 3 tumors/group). (D) IFN-γ ELISA evaluation of antigen-specific T cell responses in peripheral blood samples derived from treated mice on day 10 after tumor inoculation. Data are expressed as the mean ± SD. Results were analyzed by log-rank (Mantel-Cox) and 1-way ANOVA with Dunnett’s multiple comparisons test for data sets in A and C, respectively. *P < 0.05, **P < 0.01, ***P < 0.0001, and NS, P > 0.05.