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Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.
Notarangelo, Giulia; Spinelli, Jessica B; Perez, Elizabeth M; Baker, Gregory J; Kurmi, Kiran; Elia, Ilaria; Stopka, Sylwia A; Baquer, Gerard; Lin, Jia-Ren; Golby, Alexandra J; Joshi, Shakchhi; Baron, Heide F; Drijvers, Jefte M; Georgiev, Peter; Ringel, Alison E; Zaganjor, Elma; McBrayer, Samuel K; Sorger, Peter K; Sharpe, Arlene H; Wucherpfennig, Kai W; Santagata, Sandro; Agar, Nathalie Y R; Suvà, Mario L; Haigis, Marcia C.
Affiliation
  • 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.
  • Baker GJ; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • Kurmi K; Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Elia I; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Stopka SA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
  • Baquer G; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Lin JR; Department of Cell Biology, Blavatnik Institute, 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 Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Baron HF; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Drijvers JM; Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain.
  • Georgiev P; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ringel AE; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Zaganjor E; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • McBrayer SK; Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Sorger PK; Departments of Psychiatry and Neurology, Harvard Medical School, Boston, MA, USA.
  • Sharpe AH; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Wucherpfennig KW; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Santagata S; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Agar NYR; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Suvà ML; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Haigis MC; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Science ; 377(6614): 1519-1529, 2022 09 30.
Article in En | MEDLINE | ID: mdl-36173860
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CD8-Positive T-Lymphocytes / Carcinogenesis / Glutarates / Isocitrate Dehydrogenase / Neoplasms Limits: Animals / Humans Language: En Journal: Science Year: 2022 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CD8-Positive T-Lymphocytes / Carcinogenesis / Glutarates / Isocitrate Dehydrogenase / Neoplasms Limits: Animals / Humans Language: En Journal: Science Year: 2022 Document type: Article Affiliation country: United States