Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism
Wei Yang, Yibing Bai, Ying Xiong, Jin Zhang, Shuokai Chen, Xiaojun Zheng, Xiangbo Meng, Lunyi Li, Jing Wang, Chenguang Xu, Chengsong Yan, Lijuan 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, Wei Yang, Yibing Bai, Ying Xiong, Jin Zhang, Shuokai Chen, Xiaojun Zheng, Xiangbo Meng, Lunyi Li, Jing Wang, Chenguang Xu, Chengsong Yan, Lijuan 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
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.
Conflict of interest statement
The authors declare no competing financial interests.
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Source: PubMed