Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.
Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.
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通过调节胆固醇代谢增强 CD8 T 细胞的抗肿瘤反应
DOI：
10.1038/nature17412
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发表时间：
2016-03-31
期刊：
影响因子：
64.8
通讯作者：
Xu C
中科院分区：
文献类型：
--
作者：
Yang W;Bai Y;Xiong Y;Zhang J;Chen S;Zheng X;Meng X;Li L;Wang J;Xu C;Yan C;Wang L;Chang CC;Chang TY;Zhang T;Zhou P;Song BL;Liu W;Sun SC;Liu X;Li BL;Xu C
CD 8 + T细胞在抗肿瘤免疫中发挥核心作用，但其活性在肿瘤微环境中受到抑制。重新激活CD 8 + T细胞的细胞毒性在癌症免疫治疗中具有很大的临床意义。在这里，我们报告了一种新的机制，小鼠CD 8 + T细胞的抗肿瘤反应可以通过调节胆固醇代谢增强。通过基因消融或药理学抑制ACAT 1（一种关键的胆固醇酯化酶）来抑制T细胞中的胆固醇酯化，可增强效应子功能并增强CD 8 + T细胞的增殖，但不增强CD 4 + T细胞的增殖。这是由于CD 8 + T细胞的质膜胆固醇水平增加，这导致T细胞受体聚集和信号传导增强以及免疫突触的更有效形成。ACAT 1缺陷型CD 8 + T细胞在控制小鼠黑素瘤生长和转移方面优于野生型CD 8 + T细胞。我们使用ACAT抑制剂avasimibe治疗小鼠黑色素瘤，并观察到良好的抗肿瘤效果，avasimibe先前在临床试验中测试用于治疗动脉粥样硬化，并显示出良好的人体安全性。在控制肿瘤进展方面，阿伐麦布加抗PD-1抗体的联合治疗显示出比单药治疗更好的疗效。ACAT 1是动脉粥样硬化的既定靶点，因此也是癌症免疫治疗的潜在靶点。
CD8+ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. 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, 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 wild-type 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, 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.