Potentiating the antitumour response of CD8^sup +^ T cells by modulating cholesterol metabolism

CD8^sup +^ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment1-4. Reactivating the cytotoxicity of CD8^sup +^ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour respons...

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Published in:Nature (London) 2016-03, Vol.531 (7596), p.651
Main Authors: Yang, Wei, Bai, Yibing, Xiong, Ying, Zhang, Jin, Chen, Shuokai, Zheng, Xiaojun, Meng, Xiangbo, Li, Lunyi, Wang, Jing, Xu, Chenguang, Yan, Chengsong, Wang, Lijuan, Y Chang, Catharine C, Chang, Ta-Yuan, Zhang, Ti, Zhou, Penghui, Song, Bao-Liang, Liu, Wanli, Sun, Shao-cong, Liu, Xiaolong, Li, Bo-liang, Xu, Chenqi
Format: Article
Language:English
Subjects:
Antigens
Biosynthesis
Cancer therapies
Cholesterol
Cytokines
Cytotoxicity
Enzymes
Homeostasis
Immunology
Immunotherapy
Lymphocytes
Melanoma
Metabolism
Metastasis
Rodents
Skin cancer
T cell receptors
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Summary:CD8^sup +^ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment1-4. Reactivating the cytotoxicity of CD8^sup +^ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8^sup +^ 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 enzyme5, led to potentiated effector function and enhanced proliferation of CD8^sup +^ but not CD4^sup +^ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8^sup +^ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8^sup +^ T cells were better than wild-type CD8^sup +^ 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 profile6,7, 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature17412