Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas.
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.
Gary
G
Kohanbash
Diego A
DA
Carrera
Shruti
S
Shrivastav
Brian J
BJ
Ahn
Naznin
N
Jahan
Tali
T
Mazor
Zinal S
ZS
Chheda
Kira M
KM
Downey
Payal B
PB
Watchmaker
Casey
C
Beppler
Rolf
R
Warta
Nduka A
NA
Amankulor
Christel
C
Herold-Mende
Joseph F
JF
Costello
Hideho
H
Okada
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000201:enzymology* / Q000276:immunology; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology; D014611:Vaccination
D019496:Cancer Vaccines; D018925:Chemokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human