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

Giulia Notarangelo; Jessica B. Spinelli; Elizabeth M. Perez; Gregory J. Baker; Kiran Kurmi; Ilaria Elia; Sylwia A. Stopka; Gerard Baquer; Jia Ren Lin; Alexandra J. Golby; Shakchhi Joshi; Heide F. Baron; Jefte M. Drijvers; Peter Georgiev; Alison E. Ringel; Elma Zaganjor; Samuel K. McBrayer; Peter K. Sorger; Arlene H. Sharpe; Kai W. Wucherpfennig; Sandro Santagata; Nathalie Y.R. Agar; Mario L. Suvà; Marcia C. Haigis

doi:10.1126/science.abj5104

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

Giulia Notarangelo, Jessica B. Spinelli, Elizabeth M. Perez, Gregory J. Baker, Kiran Kurmi, Ilaria Elia, Sylwia A. Stopka, Gerard Baquer, Jia Ren Lin, Alexandra J. Golby, Shakchhi Joshi, Heide F. Baron, Jefte M. Drijvers, Peter Georgiev, Alison E. Ringel, Elma Zaganjor, Samuel K. McBrayer, Peter K. Sorger, Arlene H. Sharpe, Kai W. WucherpfennigSandro Santagata, Nathalie Y.R. Agar, Mario L. Suvà, Marcia C. Haigis

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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-g signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.

Original language	English (US)
Pages (from-to)	1519-1529
Number of pages	11
Journal	Science
Volume	377
Issue number	6614
DOIs	https://doi.org/10.1126/science.abj5104
State	Published - Sep 30 2022

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Notarangelo, G., Spinelli, J. B., Perez, E. M., Baker, G. J., Kurmi, K., Elia, I., Stopka, S. A., Baquer, G., Lin, J. R., Golby, A. J., Joshi, S., Baron, H. F., Drijvers, J. M., Georgiev, P., Ringel, A. E., Zaganjor, E., McBrayer, S. K., Sorger, P. K., Sharpe, A. H., ... Haigis, M. C. (2022). Oncometabolite D-2HG alters T cell metabolism to impair CD8⁺ T cell function. Science, 377(6614), 1519-1529. https://doi.org/10.1126/science.abj5104

Notarangelo, G, Spinelli, JB, Perez, EM, Baker, GJ, Kurmi, K, Elia, I, Stopka, SA, Baquer, G, Lin, JR, 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 2022, 'Oncometabolite D-2HG alters T cell metabolism to impair CD8⁺ T cell function', Science, vol. 377, no. 6614, pp. 1519-1529. https://doi.org/10.1126/science.abj5104

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title = "Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function",

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-g signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.",

author = "Giulia Notarangelo and Spinelli, {Jessica B.} and Perez, {Elizabeth M.} and Baker, {Gregory J.} and Kiran Kurmi and Ilaria Elia and Stopka, {Sylwia A.} and Gerard Baquer and Lin, {Jia Ren} and Golby, {Alexandra J.} and Shakchhi Joshi and Baron, {Heide F.} and Drijvers, {Jefte M.} and Peter Georgiev and Ringel, {Alison E.} and Elma Zaganjor and McBrayer, {Samuel K.} and Sorger, {Peter K.} and Sharpe, {Arlene H.} and Wucherpfennig, {Kai W.} and Sandro Santagata and Agar, {Nathalie Y.R.} and Suv{\`a}, {Mario L.} and Haigis, {Marcia C.}",

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AU - Notarangelo, Giulia

AU - Spinelli, Jessica B.

AU - Perez, Elizabeth M.

AU - Baker, Gregory J.

AU - Kurmi, Kiran

AU - Elia, Ilaria

AU - Stopka, Sylwia A.

AU - Baquer, Gerard

AU - Lin, Jia Ren

AU - Golby, Alexandra J.

AU - Joshi, Shakchhi

AU - Baron, Heide F.

AU - Drijvers, Jefte M.

AU - Georgiev, Peter

AU - Ringel, Alison E.

AU - Zaganjor, Elma

AU - McBrayer, Samuel K.

AU - Sorger, Peter K.

AU - Sharpe, Arlene H.

AU - Wucherpfennig, Kai W.

AU - Santagata, Sandro

AU - Agar, Nathalie Y.R.

AU - Suvà, Mario L.

AU - Haigis, Marcia C.

PY - 2022/9/30

Y1 - 2022/9/30

N2 - 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-g signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.

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

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