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

• DOI: 10.1038/s41467-021-22967-7
• Publication Date: 2021-05-14T10:03:17Z
• Authors: 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; Mala K. Maini
• Keywords: Sterol O-acyltransferase; Lipid droplet

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