Format

Send to

Choose Destination
Cell Rep. 2019 May 14;27(7):2063-2074.e5. doi: 10.1016/j.celrep.2019.04.022.

Acetate Promotes T Cell Effector Function during Glucose Restriction.

Author information

1
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
2
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
3
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
4
School of Life Science, Technical University of Munich, 80333 Munich, Germany.
5
ICCE Institute and Department of Medicine, Division of Molecular Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
BIOSS Center for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
8
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
9
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany. Electronic address: pearce@ie-freiburg.mpg.de.

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.

KEYWORDS:

T cell exhaustion; T cell hyporesponsiveness; T cells; acetate; acetyl-CoA synthetase; chromatin remodeling; effector functions; tumor immunity; tumor-infiltrating lymphocytes

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center