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

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.

Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

“…In line with this, in chronic hepatitis B inhibition of cholesterol esterification by the acyl-CoA:cholesterol acyltransferase (ACAT), that catalyzes the esterification of excess intracellular cholesterol for storage in lipid droplets, enhanced TCR signaling upon CD8 T cell stimulation, by reducing lipid droplet formation and diverting cholesterol to the cell membrane [69] (Figure 2, Tables 1 and 2). This strategy has been shown to be active both to enhance HBV-and HCC-specific T cell proliferation and effector functions, by optimizing cells bioenergetics, and to exert an antiviral effect by reducing HBV virions and viral particles formation in vitro [69].…”

“…In addition, the evidence that sustained responses upon PD-1 blockade treatment are detectable only in a limited proportion of HCC and chronic hepatitis B patients suggests the need of developing predictive parameters of response to treatment in order to select the patient cohorts that can benefit of check-point inhibition and to design further modulatory approaches to combine with PD-1 blockade to be used in alternative to it. Along with this line of possible strategies, inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has recently been reported to significantly improve in vitro HBV-specific CD8 T cell responsiveness to PD-1 blockade pointing to the possibility to combine metabolic and immune checkpoint modulation for the functional cure of HBV infection and HBV-related HCC [69].…”

Metabolomics Defines Complex Patterns of Dyslipidaemia in Juvenile-SLE Patients Associated with Inflammation and Potential Cardiovascular Disease Risk

“…In support, we showed that both serum and isolated VLDL and LDL from JSLE patients with active disease increased the level of lipid rafts in T-cells and B-cells associated with increased immune activation. Importantly, immune cell lipids are now recognised as targets for immunotherapies in cancer; inhibition of acetyl-CoA acetyltransferase 1 (ACAT1, cholesterol esterification enzyme that increases immune cell cholesterol levels) improves the efficacy of anti-PD1 therapy in melanoma and antiviral activity against hepatitis B due to a specific increase in CD8+ T-cell effector function against melanoma growth through lipid raft associated T-cell receptor (TCR) clustering and signalling [28,47]. Resistance to therapy in patients with ER + breast cancer is also associated with upregulated cholesterol biosynthesis enzymes which is reversed experimentally by targeting lipid biosynthesis [48].…”

“…Notably, in clinically active disease, circulating atheroprotective HDL subsets had a negative correlation, and atherogenic lipoprotein subsets (LDL/VLDL) had a positive correlation, with circulating lipids typically enriched in lipid raft microdomains (sphingomyelin, cholesterol, phosphoglycerides, phosphatidylcholine, and other cholines, Figures 3F and 4A); conversely, these correlations were reversed or decreased respectively in patients with clinically inactive disease. CD4+ T-cell, CD8+ T-cell, and B-cell lipid raft expression (assessed using the surrogate lipid raft marker cholera-toxin B [16,28]) were increased in patients with clinically +/− serologically active disease (Supplementary Figure S3) and correlated positively with disease activity measures including SLEDAI, erythrocyte sedimentation rate (ESR) and anti-double stranded DNA antibodies (dsDNA) and negatively with complement C3 (Figure 4B). Furthermore, atherogenic lipoproteins (ApoB, ApoB:A1 ratio, VLDL, IDL, and LDL) correlated positively, and atheroprotective lipoproteins (ApoA1 and HDL) correlated negatively, with lipid rafts in T-cells and B-cells (Figure 4C, Table S6), suggesting a role of lipoproteins in altering lymphocyte lipid metabolism and function.…”

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies

“…Reduced cholesterol esterification in CD8 + T cells increased plasma membrane cholesterol levels and subsequent lipid raft–associated T cell receptor clustering and signaling, thereby increasing T cell cytotoxicity against melanoma growth. ACAT inhibition can also boost the antiviral activity of CD8 + T cells against hepatitis B by promoting lipid raft signaling in vitro ( 159 ).…”