Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate.
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| Abstract | The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment. |
| Year of Publication | 2018
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| Journal | Nat Med
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| Volume | 24
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| Issue | 8
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| Pages | 1192-1203
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| Date Published | 2018 08
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| ISSN | 1546-170X
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| DOI | 10.1038/s41591-018-0095-6
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| PubMed ID | 29988124
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