Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism

Nature. 2016 Mar 31;531(7596):651-5. doi: 10.1038/nature17412. Epub 2016 Mar 16.

Abstract

CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Publication types

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

MeSH terms

  • Acetates / pharmacology*
  • Acetates / therapeutic use
  • Acetyl-CoA C-Acetyltransferase / antagonists & inhibitors
  • Acetyl-CoA C-Acetyltransferase / deficiency
  • Acetyl-CoA C-Acetyltransferase / genetics
  • Acetyl-CoA C-Acetyltransferase / metabolism
  • Animals
  • Atherosclerosis / drug therapy
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cholesterol / metabolism*
  • Esterification / drug effects
  • Female
  • Immunological Synapses / drug effects
  • Immunological Synapses / immunology
  • Immunological Synapses / metabolism
  • Immunotherapy / methods*
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / drug effects
  • Sulfonic Acids / pharmacology*
  • Sulfonic Acids / therapeutic use

Substances

  • Acetates
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Sulfonic Acids
  • avasimibe
  • Cholesterol
  • Acat1 protein, mouse
  • Acetyl-CoA C-Acetyltransferase