Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism

摘要

CD8⁺ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment^–. Reactivating the cytotoxicity of CD8⁺ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8⁺ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8⁺ but not CD4⁺ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8⁺ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8⁺ T cells were better than wild-type CD8⁺ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile^,, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.