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Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

Nathalie M Schmidt1, Peter A C Wing2, Mariana O Diniz1

  • 1Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.

Nature Communications
|May 15, 2021
PubMed

Insights

Acyl-CoA:cholesterol acyltransferase (ACAT) inhibition combats hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) by enhancing T cell function. This metabolic strategy rescues exhausted T cells, offering a potential cure for HBV and related cancers.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Virology

Background:

  • Metabolic reprogramming is crucial for T cell function in combating viral infections and cancer.
  • Acyl-CoA:cholesterol acyltransferase (ACAT) inhibition demonstrates anti-carcinogenic properties.
  • Understanding metabolic dependencies of T cells against hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) is key for therapeutic development.

Purpose of the Study:

  • To investigate the antiviral and anti-cancer effects of ACAT inhibition.
  • To determine the impact of ACAT inhibition on T cell metabolism and function in the context of HBV and HCC.
  • To explore ACAT inhibition as a therapeutic strategy for HBV and HCC.

Main Methods:

  • Inhibition of ACAT in cellular and tissue models.
  • Analysis of T cell metabolism, including neutral lipid droplets and lipid microdomains.
  • Assessment of T cell signaling, bioenergetics, and functional avidity.
  • Evaluation of HBV particle production in vitro.
  • Ex vivo treatment of dysfunctional T cells from human liver and tumor tissues.

Main Results:

  • ACAT inhibition exhibits antiviral activity against HBV and anti-tumor activity against HCC.
  • ACAT inhibition reduces neutral lipid droplets in CD8+ T cells, enhancing T cell receptor (TCR) signaling and bioenergetics.
  • Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors ex vivo.
  • ACAT inhibition improves the responsiveness of HBV-specific T cells to PD-1 blockade and enhances TCR-gene-modified T cell avidity.
  • ACAT inhibition reduces HBV virion and subviral particle production in vitro.

Conclusions:

  • ACAT inhibition acts as a metabolic checkpoint, constraining tumors and viruses while rescuing exhausted T cells.
  • ACAT inhibition is a promising therapeutic target for achieving a functional cure for HBV and HBV-related HCC.
  • Targeting ACAT offers a dual benefit of directly inhibiting viral/tumorigenic processes and restoring anti-viral/anti-tumor immunity.

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