@article{dfac9ede41894f4ba2d7ff56a19aef79,
title = "Acetate Promotes T Cell Effector Function during Glucose Restriction",
abstract = "Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer. Qiu et al. show that acetate enhances histone acetylation, chromatin accessibility, and effector function in glucose-restricted CD8+ T cells. The authors find that manipulation of acetate-handling pathways influences cytokine production of tumor-infiltrating CD8+ T cells, which could have therapeutic implications for activating CD8+ T cell effector function in the tumor microenvironment.",
keywords = "T cell exhaustion, T cell hyporesponsiveness, T cells, acetate, acetyl-CoA synthetase, chromatin remodeling, effector functions, tumor immunity, tumor-infiltrating lymphocytes",
author = "Jing Qiu and Matteo Villa and Sanin, {David E.} and Buck, {Michael D.} and David O'Sullivan and Reagan Ching and Mai Matsushita and Grzes, {Katarzyna M.} and Frances Winkler and Chang, {Chih Hao} and Curtis, {Jonathan D.} and Kyle, {Ryan L.} and {Van Teijlingen Bakker}, Nikki and Mauro Corrado and Fabian Haessler and Francesca Alfei and Joy Edwards-Hicks and Maggi, {Leonard B.} and Dietmar Zehn and Takeshi Egawa and Bertram Bengsch and {Klein Geltink}, {Ramon I.} and Thomas Jenuwein and Pearce, {Edward J.} and Pearce, {Erika L.}",
note = "Funding Information: We thank P. Allen, C. Hsieh, B. Edelson, E. Oltz, M. Colonna, D.J. Wu, and S. Huang for helpful discussions; Johan Friden for preparing the graphical abstract; Annette Patterson, Andrea Quintana, and Raima Kyle for mouse genotyping; and the Metabolomics and Deep Sequencing Cores at the Max Planck Institute of Immunobiology and Epigenetics for providing expertise for performing and analyzing experiments. This work was supported by grants from the NIH ( AI130152 to T.E., AI110481 to E.J.P. and AI091965 and CA158823 to E.L.P.) and the Max Planck Society . Funding Information: We thank P. Allen, C. Hsieh, B. Edelson, E. Oltz, M. Colonna, D.J. Wu, and S. Huang for helpful discussions; Johan Friden for preparing the graphical abstract; Annette Patterson, Andrea Quintana, and Raima Kyle for mouse genotyping; and the Metabolomics and Deep Sequencing Cores at the Max Planck Institute of Immunobiology and Epigenetics for providing expertise for performing and analyzing experiments. This work was supported by grants from the NIH (AI130152 to T.E. AI110481 to E.J.P. and AI091965 and CA158823 to E.L.P.)and the Max Planck Society. J.Q. M.V. D.E.S. M.D.B. D.O. R.C. C.-H.C. F.W. and E.L.P. designed, performed, and analyzed experiments. M.M. K.M.G. R.I.K.G. C.-H.C. J.D.C. R.L.K. N.V.T.B. M.C. F.H. F.A. and J.E.-H. provided technical assistance and critical expertise. L.B.M. D.Z. T.E. B.B. T.J. E.J.P. and E.L.P. provided reagents and conceptual input. J.Q. M.V. and E.L.P. wrote the manuscript. E.J.P. is a founder of Rheos Medicines and E.L.P. is an SAB member of ImmunoMet and a founder of Rheos Medicines. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = may,
day = "14",
doi = "10.1016/j.celrep.2019.04.022",
language = "English",
volume = "27",
pages = "2063--2074.e5",
journal = "Cell Reports",
issn = "2211-1247",
number = "7",
}