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

Schmidt, N. M. et al. (2021) Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint. Nature Communications, 12, 2814. (doi: 10.1038/s41467-021-22967-7) (PMID:33990561) (PMCID:PMC8121939)

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.

• Item Type: Articles
• Additional Information: This work was funded by a Wellcome Trust Investigator Award (214191/Z/18/Z) to M.K.M., Cancer Research UK project grant (26603) to M.K.M., T.M. and H.J.S., Cancer Research UK HUNTER: Hepatocellular Carcinoma Expediter Network to M.K.M. and T.M., a Wellcome Trust Investigator Award (200838/Z/16/Z) to J.A.M., an MRC project grant (MR/R022011/1) to J.A.M., and a DFG Research Fellowship (SCHM3310/1-1) to N.M.S.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Grove, Dr Joe
• Authors: Schmidt, N. M., Wing, P. A. C., Diniz, M. O., Pallett, L. J., Swadling, L., Harris, J. M., Burton, A. R., Jeffery-Smith, A., Zakeri, N., Amin, O. E., Kucykowicz, S., Heemskerk, M. H., Davidson, B., Meyer, T., Grove, J., Stauss, H. J., Pineda-Torra, I., Jolly, C., Jury, E. C., McKeating, J. A., and Maini, M. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 2814
• Publisher Policy: Reproduced under a Creative Commons License