期刊
SCIENCE
卷 377, 期 6614, 页码 1519-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abj5104
关键词
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资金
- National Science Foundation (NSF) Graduate Research Fellowship Program [DGE1745303]
- European Molecular Biology Organization [ALTF107802017]
- Life Sciences Research Foundation
- National Institutes of Health (NIH) [R01CA213062]
- Ludwig Center at Harvard Medical School
- NIH [U54-CA225088, 1P01CA236749, U54-CA210180, P41-EB028741, T32EB025823]
- NSF Graduate Research Fellowship Program [DGE1745303]
- Massachusetts Life Sciences Center
- Marie Sklodowska-Curie grant [713679]
- European Union
- Universitat Rovira i Virgili
- Marie Curie Actions (MSCA) [713679] Funding Source: Marie Curie Actions (MSCA)
Gain-of-function mutations in IDH result in the production of oncometabolite D-2HG, which promotes tumorigenesis by affecting the metabolism and antitumor functions of CD8(+) T cells.
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-g signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.
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