Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.
Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.
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通过 microRNA-200/ZEB1 轴控制肿瘤细胞 PD-L1 表达和瘤内免疫抑制来调节转移。
DOI：
10.1038/ncomms6241
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发表时间：
2014-10-28
影响因子：
16.6
通讯作者：
Qin, F. Xiao-Feng
中科院分区：
文献类型：
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作者：
Chen, Limo;Gibbons, Don L.;Goswami, Sangeeta;Cortez, Maria Angelica;Ahn, Young-Ho;Byers, Lauren A.;Zhang, Xuejun;Yi, Xiaohui;Dwyer, David;Lin, Wei;Diao, Lixia;Wang, Jing;Roybal, Jonathon D.;Patel, Mayuri;Ungewiss, Christin;Peng, David;Antonia, Scott;Mediavilla-Varela, Melanie;Robertson, Gordon;Jones, Steve;Suraokar, Milind;Welsh, James W.;Erez, Baruch;Wistuba, Ignacio I.;Chen, Lieping;Peng, Di;Wang, Shanshan;Ullrich, Stephen E.;Heymach, John V.;Kurie, Jonathan M.;Qin, F. Xiao-Feng
肿瘤浸润淋巴细胞（TIL）的免疫抑制是晚期癌症的共同特征，但其生物学基础尚不清楚。我们在这里证明了上皮到间质转化（EMT）和CD8+ TIL免疫抑制之间的分子联系，这是癌症进展的两个关键驱动因素。我们发现microRNA-200 (miR-200)，一种EMT和转移的细胞自主抑制因子，靶向PD-L1。此外，作为EMT激活剂和miR-200的转录抑制因子，ZEB1可以缓解miR-200对肿瘤细胞PD-L1的抑制，从而导致CD8+ T细胞的免疫抑制和转移。这些发现得到了多个人类肺癌数据集中EMT评分、miR-200水平和PD-L1表达之间的强大相关性的支持。除了揭示EMT和T细胞功能障碍之间的联系外，这些发现还表明ZEB1通过迄今为止未被发现的细胞非自主机制促进转移，并表明由EMT激活剂驱动恶性进展的患者亚组可能对PD-L1拮抗剂治疗有反应。
Immunosuppression of tumor-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8+ TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumor cells, leading to CD8+ T cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.
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影响因子：
3.7
作者：
Kong D;Banerjee S;Ahmad A;Li Y;Wang Z;Sethi S;Sarkar FH
通讯作者：
Sarkar FH
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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通过PD-1-PD-1配体阻滞来振兴耗尽的HIV特异性T细胞。
影响因子：
15.3
作者：
Freeman, Gordon J.;Wherry, E. John;Ahmed, Rafi;Sharpe, Arlene H.
通讯作者：
Sharpe, Arlene H.
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
32.4
作者：
DIGHE, AS;RICHARDS, E;SCHREIBER, RD
通讯作者：
SCHREIBER, RD