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论文题目: Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism
英文论文题目: Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism
第一作者: Yang, W; Bai, YB; Xiong, Y; Zhang, J; Chen, SK; Zheng, XJ; Meng, XB; Li, LY; Wang, J; Xu, CG; Yan, CS; Wang, LJ; Chang, CCY; Chang, TY; Zhang, T; Zhou, PH; Song, BL; Liu, WL; Sun, SC; Liu, XL; Li, BL; Xu, CQ
英文第一作者: Yang, W; Bai, YB; Xiong, Y; Zhang, J; Chen, SK; Zheng, XJ; Meng, XB; Li, LY; Wang, J; Xu, CG; Yan, CS; Wang, LJ; Chang, CCY; Chang, TY; Zhang, T; Zhou, PH; Song, BL; Liu, WL; Sun, SC; Liu, XL; Li, BL; Xu, CQ
联系作者: Xu, CQ (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol,Natl Ctr Prot Sci Shanghai, Shanghai Sci Res Ctr,Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
英文联系作者: Xu, CQ (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol,Natl Ctr Prot Sci Shanghai, Shanghai Sci Res Ctr,Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
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发表年度: 2016
卷: 531
期: 7596
页码: 651-+
摘要: 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.
英文摘要: 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.
刊物名称: NATURE
英文刊物名称: NATURE
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学科: Multidisciplinary Sciences
英文学科: Multidisciplinary Sciences
影响因子: 40.137
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论文类别: Article
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