Acetate Promotes T Cell Effector Function during Glucose Restriction

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetate-CoA Ligase / immunology*
  • Acetates / immunology*
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Glucose / immunology*
  • Humans
  • Interferon-gamma / immunology*
  • Mice
  • Neoplasm Proteins / immunology*
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / pathology

Substances

  • Acetates
  • IFNG protein, mouse
  • Neoplasm Proteins
  • Interferon-gamma
  • Acetate-CoA Ligase
  • Glucose