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| Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism | |
Yang, Wei1; Bai, Yibing1; Xiong, Ying2; Zhang, Jin1; Chen, Shuokai1; Zheng, Xiaojun3; Meng, Xiangbo1; Li, Lunyi1; Wang, Jing4; Xu, Chenguang4; Yan, Chengsong1; Wang, Lijuan2; Chang, Catharine C. Y.5; Chang, Ta-Yuan5; Zhang, Ti6; Zhou, Penghui7; Song, Bao-Liang8; Liu, Wanli4; Sun, Shao-Cong9; Liu, Xiaolong10; Li, Bo-liang2; Xu, Chenqi1,11 
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| 2016-03-31 | |
| Source Publication | NATURE
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| ISSN | 0028-0836 |
| Volume | 531Issue:7596Pages:651-+ |
| Status | 已发表 |
| DOI | 10.1038/nature17412 |
| Abstract | 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. |
| Indexed By | SCI |
| Language | 英语 |
| Funding Project | MOST[2011CB910901] ; MOST[2012CB910804] |
| WOS Research Area | Science & Technology - Other Topics |
| WOS Subject | Multidisciplinary Sciences |
| WOS ID | WOS:000373027400041 |
| Publisher | NATURE PUBLISHING GROUP |
| WOS Keyword | THYMOCYTE POSITIVE SELECTION ; CANCER-IMMUNOTHERAPY ; ACYL-COENZYME ; IMMUNOLOGICAL SYNAPSE ; IMMUNE MODULATION ; MEMBRANE-BINDING ; ACAT INHIBITORS ; RECEPTOR ; ACTIVATION ; DOMAIN |
| Original Document Type | Article |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1891 |
| Collection | 生命科学与技术学院_特聘教授组_许琛琦组 |
| Corresponding Author | Li, Bo-liang; Xu, Chenqi |
| Affiliation | 1.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 2.Chinese Acad Sci, Shanghai Inst Biol Sci, CAS Ctr Excellence Mol Cell Sci, State Key Lab Mol Biol,Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China 4.Tsinghua Univ, Collaborat Innovat Ctr Infect Dis, Sch Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China 5.Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA 6.Second Mil Med Univ, ChangZheng Hosp, Rheumatol & Immunol Dept, Shanghai 200433, Peoples R China 7.Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China 8.Wuhan Univ, Coll Life Sci, Wuhan 430072, Hubei Province, Peoples R China 9.Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77054 USA 10.Chinese Acad Sci, Shanghai Inst Biol Sci, CAS Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol,Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China 11.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China |
| Corresponding Author Affilication | School of Life Science and Technology |
| Recommended Citation GB/T 7714 | Yang, Wei,Bai, Yibing,Xiong, Ying,et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism[J]. NATURE,2016,531(7596):651-+. |
| APA | Yang, Wei.,Bai, Yibing.,Xiong, Ying.,Zhang, Jin.,Chen, Shuokai.,...&Xu, Chenqi.(2016).Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.NATURE,531(7596),651-+. |
| MLA | Yang, Wei,et al."Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism".NATURE 531.7596(2016):651-+. |
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