W95 - Targeting Cholesterol Metabolism as a Novel Immune Checkpoint in Viral Infections and Cancer

Metabolic targets may provide novel strategies to complement existing classical checkpoints in order to boost the highly exhausted T cells directed against viruses and tumours. Recent studies demonstrated that inhibition of acyl-coenzyme A:cholesterol acyltransferases (ACAT) can both enhance murine anti-tumour CD8+ T cell efficacy and mediate a direct antitumour effect. We showed that reduced formation of membrane lipid microdomains is a feature of PD-1^hi exhausted T cells. We therefore investigated the potential for rescue of exhausted human virus-and tumour-specific T cell responses by modulation of cholesterol metabolism and lipid microdomain formation. We found that ACAT inhibition could enhance the expansion of functional virus-specific T cells from donors with chronic hepatitis B virus (HBV) or acute SARS-CoV-2 infection. ACAT inhibition also boosted hepatocellular carcinoma (HCC)-specific T cell responses directly isolated from human liver and liver tumour lesions in the majority of patients. Responding T cells showed increased lipid microdomain formation, reduced lipid droplets, enhanced T cell receptor (TCR) signaling and TCR-independent bioenergetic reprogramming. ACAT inhibition had a complementary effect with other immunotherapies, with increased responsiveness to PD-1 blockade and enhanced functional avidity of T cells genetically engineered to recognize HBV and tumour cells.
Taken together, modulating cholesterol metabolism by inhibition of ACAT is a promising therapeutic target, enhancing immune responses in acute and chronic infection and in cancer.