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

Article

关键词: THYMOCYTE POSITIVE SELECTION;    CANCER-IMMUNOTHERAPY;    ACYL-COENZYME;    IMMUNOLOGICAL SYNAPSE;    IMMUNE MODULATION;    MEMBRANE-BINDING;    ACAT INHIBITORS;    RECEPTOR;    ACTIVATION;    DOMAIN;   

DOI  :  10.1038/nature17412

来源: SCIE

【 摘 要 】

CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment(1-4). 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(5), 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 wildtype 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(6,7), 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.

【 授权许可】

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