Title | Oncometabolite d-2HG alters T cell metabolism to impair CD8 T cell function. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Notarangelo G, Spinelli JB, Perez EM, Baker GJ, Kurmi K, Elia I, Stopka SA, Baquer G, Lin J-R, Golby AJ, Joshi S, Baron HF, Drijvers JM, Georgiev P, Ringel AE, Zaganjor E, McBrayer SK, Sorger PK, Sharpe AH, Wucherpfennig KW, Santagata S, Agar NYR, Suvà ML, Haigis MC |
Journal | Science |
Volume | 377 |
Issue | 6614 |
Pagination | 1519-1529 |
Date Published | 2022 Sep 30 |
ISSN | 1095-9203 |
Keywords | Animals, Carcinogenesis, CD8-Positive T-Lymphocytes, Gain of Function Mutation, Glutarates, Humans, Interferon-gamma, Isocitrate Dehydrogenase, L-Lactate Dehydrogenase, Mice, Neoplasms |
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 mutant gliomas. |
DOI | 10.1126/science.abj5104 |
Alternate Journal | Science |
PubMed ID | 36173860 |
PubMed Central ID | PMC9629749 |
Grant List | P01 CA236749 / CA / NCI NIH HHS / United States R01 CA213062 / CA / NCI NIH HHS / United States P41 EB028741 / EB / NIBIB NIH HHS / United States U54 CA210180 / CA / NCI NIH HHS / United States T32 EB025823 / EB / NIBIB NIH HHS / United States U54 CA225088 / CA / NCI NIH HHS / United States |