Oncometabolite d-2HG alters T cell metabolism to impair CD8 + T cell function.

Autor: Notarangelo G; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Spinelli JB; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Perez EM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.; Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Baker GJ; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA., Kurmi K; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Elia I; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Stopka SA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Baquer G; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain., Lin JR; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA., Golby AJ; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Joshi S; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Baron HF; Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Departments of Psychiatry and Neurology, Harvard Medical School, Boston, MA, USA., Drijvers JM; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Georgiev P; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Ringel AE; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Zaganjor E; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., McBrayer SK; Children's Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Sorger PK; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA., Sharpe AH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Wucherpfennig KW; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA., Santagata S; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Agar NYR; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Suvà ML; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA., Haigis MC; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2022 Sep 30; Vol. 377 (6614), pp. 1519-1529. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1126/science.abj5104
Abstrakt: 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.
Databáze: MEDLINE
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