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

机译：通过调节胆固醇代谢增强CD8（+）T细胞的抗肿瘤反应

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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.
机译：CD8（+）T细胞在抗肿瘤免疫中具有重要作用，但在肿瘤微环境中其活性受到抑制（1-4）。重新激活CD8（+）T细胞的细胞毒性在癌症免疫治疗中具有重大的临床意义。在这里我们报告了一种新的机制，通过它可以通过调节胆固醇代谢来增强小鼠CD8（+）T细胞的抗肿瘤反应。通过遗传消融或药理学抑制ACAT1（一种关键的胆固醇酯化酶）（5）抑制T细胞中的胆固醇酯化，可增强效应子功能并增强CD8（+）而非CD4（+）T细胞的增殖。这是由于CD8（+）T细胞的质膜胆固醇水平增加，导致T细胞受体簇集和信号传导增强以及免疫突触的更有效形成。在控制小鼠黑色素瘤生长和转移方面，ACAT1缺陷型CD8（+）T细胞优于野生型CD8（+）T细胞。我们使用了ACAT抑制剂阿瓦西米贝（avasimibe）来治疗小鼠黑色素瘤，该药物先前已在临床试验中用于治疗动脉粥样硬化并显示出良好的人体安全性（6,7），并具有良好的抗肿瘤作用。阿瓦西米贝联合抗PD-1抗体的联合治疗在控制肿瘤进展方面显示出比单一疗法更好的疗效。因此，ACAT1是动脉粥样硬化的既定靶标，也是癌症免疫疗法的潜在靶标。

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  • 来源
    《Nature》 |2016年第7596期|651-655|共5页
  • 作者

    Yang Wei; Bai Yibing; Xiong Ying; Zhang Jin; Chen Shuokai; Zheng Xiaojun; Meng Xiangbo; Li Lunyi; Wang Jing; Xu Chenguang; Yan Chengsong; Wang Lijuan; Chang Catharine C. Y.; Chang Ta-Yuan; Zhang Ti; Zhou Penghui; Song Bao-Liang; Liu Wanli; Sun Shao-Cong; Liu Xiaolong; Li Bo-liang; Xu Chenqi;

  • 作者单位

    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;

    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;

    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;

    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;

    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;

    Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China;

    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;

    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;

    Tsinghua Univ, Collaborat Innovat Ctr Infect Dis, Sch Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China;

    Tsinghua Univ, Collaborat Innovat Ctr Infect Dis, Sch Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China;

    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;

    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;

    Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA;

    Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH USA;

    Second Mil Med Univ, ChangZheng Hosp, Rheumatol & Immunol Dept, Shanghai 200433, Peoples R China;

    Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China;

    Wuhan Univ, Coll Life Sci, Wuhan 430072, Hubei Province, Peoples R China;

    Tsinghua Univ, Collaborat Innovat Ctr Infect Dis, Sch Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China;

    Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77054 USA;

    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;

    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;

    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|ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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