Targeting T cell cholesterol metabolism for tumor immunotherapy

来源 :中国生物化学与分子生物学会2016年全国学术会议 | 被引量 : 0次 | 上传用户:fijihi
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  CD8+T cells have a central role in antitumor immunity,but their activity is suppressed in the tumor 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 antitumor 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 signaling 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 antitumor effect.A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumor progression.ACAT1,an established target for atherosclerosis,is therefore also a potential target for cancer immunotherapy.
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