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

doi:10.1038/nature17412

	Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism
	Yang, Wei 1; Bai, Yibing 1; Xiong, Ying 2; Zhang, Jin 1; Chen, Shuokai 1; Zheng, Xiaojun 3; Meng, Xiangbo 1; Li, Lunyi 1; Wang, Jing 4; Xu, Chenguang 4; Yan, Chengsong 1; Wang, Lijuan 2; Chang, Catharine C. Y.5; Chang, Ta-Yuan 5; Zhang, Ti 6; Zhou, Penghui 7; Song, Bao-Liang 8; Liu, Wanli 4; Sun, Shao-Cong 9; Liu, Xiaolong 10; Li, Bo-liang 2; Xu, Chenqi1,11
	2016-03-31
发表期刊	NATURE
ISSN	0028-0836
卷号	531 期号:7596 页码:651-+
发表状态	已发表
DOI	10.1038/nature17412
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.
收录类别	SCI
语种	英语
资助项目	MOST[2011CB910901] ; MOST[2012CB910804]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000373027400041
出版者	NATURE PUBLISHING GROUP
WOS关键词	THYMOCYTE POSITIVE SELECTION ; CANCER-IMMUNOTHERAPY ; ACYL-COENZYME ; IMMUNOLOGICAL SYNAPSE ; IMMUNE MODULATION ; MEMBRANE-BINDING ; ACAT INHIBITORS ; RECEPTOR ; ACTIVATION ; DOMAIN
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1891
专题	生命科学与技术学院_特聘教授组_许琛琦组
通讯作者	Li, Bo-liang; Xu, Chenqi
作者单位	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
通讯作者单位	生命科学与技术学院
推荐引用方式 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-+.