Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function
Abstract
Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of D-2-hydroxyglutarate (D-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of D-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite D-2HG with its enantiomer, L-2HG, and found that tumor-derived D-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of D-2HG. D-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.
- Publication:
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Science
- Pub Date:
- September 2022
- DOI:
- 10.1126/science.abj5104
- Bibcode:
- 2022Sci...377.1519N
- Keywords:
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- BIOCHEM; MEDICINE