Potentiating the antitumour response of CD8 + T cells by modulating cholesterol metabolism
Wei Yang,Bai Yibing,Ying Xiong,Jin Zhang,S.H. Chen,Xiaojun Zheng,Xiangbo Meng,L. Li,Jing Wang,Chenguang Xu,Chengsong Yan,Li-Juan Wang,Catharine C.Y. Chang,Ta-Yuan Chang,Ti Zhang,Penghui Zhou,Bao-Liang Song,Wanli Liu,Shao Cong Sun,Xiaolong Liu,Bo-Liang Li,Chenqi Xu,Chenqi Xu +22 more
TLDR
A new mechanism by which the antitumour response of mouse CD8+ T cells can be potentiated by modulating cholesterol metabolism is reported, which indicates ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.Abstract:
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.read more
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