Oncometabolite <scp>d</scp> -2HG alters T cell metabolism to impair CD8 <sup>+</sup> T cell function-Reference-Cited by-全球学者库

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

Published:2022-09-30 Issue:6614 Volume:377 Page:1519-1529
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Notarangelo Giulia¹^ORCID,Spinelli Jessica B.¹^ORCID,Perez Elizabeth M.²³⁴^ORCID,Baker Gregory J.⁵⁶^ORCID,Kurmi Kiran¹^ORCID,Elia Ilaria¹^ORCID,Stopka Sylwia A.⁷⁸^ORCID,Baquer Gerard⁷⁹^ORCID,Lin Jia-Ren⁵^ORCID,Golby Alexandra J.⁷^ORCID,Joshi Shakchhi¹,Baron Heide F.¹⁰¹¹^ORCID,Drijvers Jefte M.¹¹²^ORCID,Georgiev Peter¹¹²^ORCID,Ringel Alison E.¹^ORCID,Zaganjor Elma¹^ORCID,McBrayer Samuel K.¹³^ORCID,Sorger Peter K.⁵^ORCID,Sharpe Arlene H.²¹²^ORCID,Wucherpfennig Kai W.²¹²¹⁴¹⁵^ORCID,Santagata Sandro⁵⁶¹⁶^ORCID,Agar Nathalie Y. R.⁷⁸¹⁷^ORCID,Suvà Mario L.²³^ORCID,Haigis Marcia C.¹^ORCID

Affiliation:

1. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

2. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

3. Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.

4. Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

5. Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

6. Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.

7. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

8. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

9. Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain.

10. Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

11. Departments of Psychiatry and Neurology, Harvard Medical School, Boston, MA, USA.

12. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

13. Children’s Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

14. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.

15. Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA.

16. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

17. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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