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

Authors :
Bai Yibing
Li-Juan Wang
Chengsong Yan
Catharine C.Y. Chang
S.H. Chen
Ying Xiong
Bao-Liang Song
Chenqi Xu
Xiaolong Liu
Jing Wang
Ti Zhang
Wanli Liu
Chenguang Xu
Xiangbo Meng
Wei Yang
L. Li
Shao Cong Sun
Jin Zhang
Ta-Yuan Chang
Bo-Liang Li
Xiaojun Zheng
Penghui Zhou
Source :
Nature. 531(7596)
Publication Year :
2015

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.

Details

ISSN :
14764687
Volume :
531
Issue :
7596
Database :
OpenAIRE
Journal :
Nature
Accession number :
edsair.doi.dedup.....4d3084a357cfa7351fb152fb3566007a