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

Nathalie M. Schmidt, Peter A. C. Wing, Mariana O. Diniz, Laura J. Pallett, Leo Swadling, James M. Harris, Alice R. Burton, Anna Jeffery-Smith, Nekisa Zakeri, Oliver E. Amin, Stephanie Kucykowicz, Mirjam H. Heemskerk, Brian Davidson, Tim Meyer, Joe Grove, Hans J. Stauss, Ines Pineda-Torra, Clare Jolly, Elizabeth C. Jury, Jane A. McKeating and Mala K. Maini ()
Additional contact information
Nathalie M. Schmidt: University College London
Peter A. C. Wing: Oxford University
Mariana O. Diniz: University College London
Laura J. Pallett: University College London
Leo Swadling: University College London
James M. Harris: Oxford University
Alice R. Burton: University College London
Anna Jeffery-Smith: University College London
Nekisa Zakeri: University College London
Oliver E. Amin: University College London
Stephanie Kucykowicz: University College London
Mirjam H. Heemskerk: Leiden University Medical Center
Brian Davidson: University College London
Tim Meyer: Royal Free London NHS Foundation Trust
Joe Grove: University College London
Hans J. Stauss: University College London
Ines Pineda-Torra: University College London
Clare Jolly: University College London
Elizabeth C. Jury: University College London
Jane A. McKeating: Oxford University
Mala K. Maini: University College London

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22967-7

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