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Publication Detail
Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Schmidt NM, Wing PAC, Diniz MO, Pallett LJ, Swadling L, Harris JM, Burton AR, Jeffery-Smith A, Zakeri N, Amin OE, Kucykowicz S, Heemskerk MH, Davidson B, Meyer T, Grove J, Stauss HJ, Pineda-Torra I, Jolly C, Jury EC, McKeating JA, Maini MK
  • Publisher:
    Nature Publishing Group
  • Publication date:
    14/05/2021
  • Pagination:
    2814
  • Journal:
    Nature Communications
  • Volume:
    12
  • Issue:
    1
  • Status:
    Published online
  • Country:
    England
  • Print ISSN:
    2041-1723
  • PII:
    10.1038/s41467-021-22967-7
  • Language:
    eng
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.
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