Oncometabolite d -2HG alters T cell metabolism to impair CD8 + T cell function
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...
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| Published in | Science (American Association for the Advancement of Science) Vol. 377; no. 6614; pp. 1519 - 1529 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
30.09.2022
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0036-8075 1095-9203 1095-9203 |
| DOI | 10.1126/science.abj5104 |
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| 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.
Cancer-causing mutations in isocitrate dehydrogenase cause accumulation of the metabolite
d
-2-hydroxyglutarate (
d
-2HG). Notarangelo
et al
. showed that such high concentrations of
d
-2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells (see the Perspective by Nathan). Inhibition of this metabolic enzyme altered glucose metabolism in the T cells and inhibited their proliferation, cytokine production, and ability to kill target cells. The authors propose that in addition to its known cell-autonomous cancer-promoting effects,
d
-2HG may also have immunosuppressive activity. —LBR
Excess metabolite from cancer cells may hinder antitumor immunity. |
|---|---|
| AbstractList | 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. Oncometabolite targets T cellsCancer-causing mutations in isocitrate dehydrogenase cause accumulation of the metabolite d-2-hydroxyglutarate (d-2HG). Notarangelo et al. showed that such high concentrations of d-2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells (see the Perspective by Nathan). Inhibition of this metabolic enzyme altered glucose metabolism in the T cells and inhibited their proliferation, cytokine production, and ability to kill target cells. The authors propose that in addition to its known cell-autonomous cancer-promoting effects, d-2HG may also have immunosuppressive activity. —LBR 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. Cancer-causing mutations in isocitrate dehydrogenase cause accumulation of the metabolite d -2-hydroxyglutarate ( d -2HG). Notarangelo et al . showed that such high concentrations of d -2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells (see the Perspective by Nathan). Inhibition of this metabolic enzyme altered glucose metabolism in the T cells and inhibited their proliferation, cytokine production, and ability to kill target cells. The authors propose that in addition to its known cell-autonomous cancer-promoting effects, d -2HG may also have immunosuppressive activity. —LBR Excess metabolite from cancer cells may hinder antitumor immunity. 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.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. 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. |
| Author | Lin, Jia-Ren Sorger, Peter K. Notarangelo, Giulia Spinelli, Jessica B. Haigis, Marcia C. Elia, Ilaria Drijvers, Jefte M. Zaganjor, Elma Sharpe, Arlene H. Kurmi, Kiran Agar, Nathalie Y. R. Santagata, Sandro Suvà, Mario L. Perez, Elizabeth M. Ringel, Alison E. Joshi, Shakchhi Stopka, Sylwia A. Baron, Heide F. Wucherpfennig, Kai W. Golby, Alexandra J. McBrayer, Samuel K. Georgiev, Peter Baker, Gregory J. Baquer, Gerard |
| AuthorAffiliation | 13 Children’s Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA 4 Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA 2 Broad Institute of MIT and Harvard, Cambridge, MA, USA 12 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA 1 Department of Cell Biology, Blavatnik Institute, 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 15 Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA 14 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA 6 Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA 10 Chemical Neur |
| AuthorAffiliation_xml | – name: 5 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA – name: 4 Department of Systems Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – name: 12 Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – name: 14 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA – name: 2 Broad Institute of MIT and Harvard, Cambridge, MA, USA – name: 15 Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA – name: 6 Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA – name: 3 Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA – name: 9 Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain – name: 16 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA – name: 10 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA – name: 11 Departments of Psychiatry and Neurology, Harvard Medical School, Boston, MA, USA – name: 8 Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA – name: 7 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA – name: 1 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – name: 13 Children’s Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA – name: 17 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA |
| Author_xml | – sequence: 1 givenname: Giulia orcidid: 0000-0003-3805-1834 surname: Notarangelo fullname: Notarangelo, Giulia organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 2 givenname: Jessica B. orcidid: 0000-0003-3657-4578 surname: Spinelli fullname: Spinelli, Jessica B. organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 3 givenname: Elizabeth M. orcidid: 0000-0002-6198-8329 surname: Perez fullname: Perez, Elizabeth M. organization: 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 – sequence: 4 givenname: Gregory J. orcidid: 0000-0002-5196-3961 surname: Baker fullname: Baker, Gregory J. organization: Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA., Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA – sequence: 5 givenname: Kiran orcidid: 0000-0002-1345-0196 surname: Kurmi fullname: Kurmi, Kiran organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 6 givenname: Ilaria orcidid: 0000-0003-0922-9429 surname: Elia fullname: Elia, Ilaria organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 7 givenname: Sylwia A. orcidid: 0000-0003-3761-6899 surname: Stopka fullname: Stopka, Sylwia A. organization: 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 – sequence: 8 givenname: Gerard orcidid: 0000-0002-4433-4972 surname: Baquer fullname: Baquer, Gerard organization: Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA., Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain – sequence: 9 givenname: Jia-Ren orcidid: 0000-0003-4702-7705 surname: Lin fullname: Lin, Jia-Ren organization: Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA – sequence: 10 givenname: Alexandra J. orcidid: 0000-0001-8461-9561 surname: Golby fullname: Golby, Alexandra J. organization: Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA – sequence: 11 givenname: Shakchhi surname: Joshi fullname: Joshi, Shakchhi organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 12 givenname: Heide F. orcidid: 0000-0003-1575-4529 surname: Baron fullname: Baron, Heide F. organization: Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Departments of Psychiatry and Neurology, Harvard Medical School, Boston, MA, USA – sequence: 13 givenname: Jefte M. orcidid: 0000-0002-5675-5643 surname: Drijvers fullname: Drijvers, Jefte M. organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 14 givenname: Peter orcidid: 0000-0002-4613-1255 surname: Georgiev fullname: Georgiev, Peter organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 15 givenname: Alison E. orcidid: 0000-0002-6451-9376 surname: Ringel fullname: Ringel, Alison E. organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 16 givenname: Elma orcidid: 0000-0003-0600-7417 surname: Zaganjor fullname: Zaganjor, Elma organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 17 givenname: Samuel K. orcidid: 0000-0001-9361-675X surname: McBrayer fullname: McBrayer, Samuel K. organization: Children’s Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA – sequence: 18 givenname: Peter K. orcidid: 0000-0002-3364-1838 surname: Sorger fullname: Sorger, Peter K. organization: Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA – sequence: 19 givenname: Arlene H. orcidid: 0000-0002-9736-2109 surname: Sharpe fullname: Sharpe, Arlene H. organization: Broad Institute of MIT and Harvard, Cambridge, MA, USA., Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA – sequence: 20 givenname: Kai W. orcidid: 0000-0002-1829-302X surname: Wucherpfennig fullname: Wucherpfennig, Kai W. organization: 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 – sequence: 21 givenname: Sandro orcidid: 0000-0002-7528-9668 surname: Santagata fullname: Santagata, Sandro organization: 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 – sequence: 22 givenname: Nathalie Y. R. orcidid: 0000-0003-3149-3146 surname: Agar fullname: Agar, Nathalie Y. R. organization: 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 – sequence: 23 givenname: Mario L. orcidid: 0000-0001-9898-5351 surname: Suvà fullname: Suvà, Mario L. organization: Broad Institute of MIT and Harvard, Cambridge, MA, USA., Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA – sequence: 24 givenname: Marcia C. orcidid: 0000-0003-2530-2681 surname: Haigis fullname: Haigis, Marcia C. organization: Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/36173860$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Present address: Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium. Author contributions: G.N., J.B.S., and M.C.H. conceived the project. G.N. performed most of the experiments. I.E., J.M.D., S.J., H.F.B., P.G., E.Z., A.E.R., A.H.S., S.K.M., and K.K. provided research assistance. K.K. performed RNA-sequencing analyses. E.M.P., K.W.W., and M.L.S. generated and analyzed single-cell RNA-sequencing datasets. A.J.G. obtained human glioma tissue samples and oversaw human subject research. G.J.B., G.B., S.A.S., J.L., P.K.S., S.S., and N.Y.R.A. oversaw, performed, and analyzed the MSI and CyCIF studies. G.N. and M.H. analyzed and interpreted the data. G.N. and M.H. wrote the manuscript with input from all authors. Present address: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA, and Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Present address: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. Present address: Abata Therapeutics, Cambridge, MA, USA. |
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| Snippet | Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of
d
-2-hydroxyglutarate (
d
-2HG), an oncometabolite... Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that... Oncometabolite targets T cellsCancer-causing mutations in isocitrate dehydrogenase cause accumulation of the metabolite d-2-hydroxyglutarate (d-2HG).... |
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| SubjectTerms | Animals Cancer Carcinogenesis - genetics Carcinogenesis - metabolism CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell proliferation Cytokines Dehydrogenase Gain of Function Mutation Glucose metabolism Glutarates - metabolism Humans Immunosuppressive agents Interferon-gamma - metabolism Isocitrate dehydrogenase Isocitrate Dehydrogenase - genetics Isocitrate Dehydrogenase - metabolism L-Lactate dehydrogenase L-Lactate Dehydrogenase - antagonists & inhibitors L-Lactate Dehydrogenase - metabolism Lactate dehydrogenase Lactic acid Lymphocytes Lymphocytes T Metabolites Mice Mutation Neoplasms - genetics Neoplasms - immunology Neoplasms - metabolism |
| Title | Oncometabolite d -2HG alters T cell metabolism to impair CD8 + T cell function |
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