Journal
NATURE
Volume 531, Issue 7596, Pages 651-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature17412
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Funding
- NSFC [31370860, 31425009, 31530022, 31271377, 31400745]
- CAS [XDB08020100, KSCX2-EW-J-11]
- China Postdoctoral Science Foundation [2014M561533, 2014T70440]
- NIH [HL 60306]
- MOST [2011CB910901, 2012CB910804]
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CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment(1-4). 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(5), 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 wildtype 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(6,7), 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.
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