Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T\xa0cell metabolic checkpoint

Nathalie M Schmidt,Mariana O Diniz,Alice R Burton,Jane A Mckeating,Nekisa Zakeri,Clare Jolly,Hans J Stauss,Stephanie Kucykowicz,James Michael Harris ,Elizabeth C Jury,Tim Meyer,Mirjam H.m Heemskerk ,Oliver E Amin,Anna Jeffery-Smith,Peter Ac Wing ,Joe Grove,Leo Swadling,Inés Pineda-Torra ,Laura J Pallett,Brian R Davidson ,Mala K Maini

doi:10.1038/s41467-021-22967-7

Abstract

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.

Highlights

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints
We investigated the impact of inhibiting cholesterol esterification on the dysfunctional Hepatitis B virus (HBV)-specific CD8+ T cell response that is characteristic of chronic HBV infection (CHB)
The addition of an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor during the culture of peripheral blood mononuclear cells (PBMC) from patients with CHB increased the proportion of CD8+ T cells producing the antiviral cytokine interferon γ (IFNγ) in response to overlapping peptides (OLP) (Fig. 1a; gating strategy Supplementary Fig. 1a)

Summary

Introduction

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC. We find that ACAT inhibition drives metabolic re-modelling, resulting in enhanced expansion and functionality of human CD8+ T cells directed against HBV and HCC, sampled directly from the site of disease. We show additional therapeutic benefits of this approach include its capacity to act in a complementary manner to PD-1 blockade, to enhance the functional avidity of TCR-gene-modified T cells and to exert antiviral effects against HBV

Methods

Results

Conclusion