Epithelial-mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer
Epithelial-mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer
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DOI：
10.1172/jci97611
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发表时间：
2018-04-02
影响因子：
15.9
通讯作者：
Keshamouni, Venkateshwar G.
中科院分区：
文献类型：
--
作者：
Chockley, Peter J.;Chen, Jun;Keshamouni, Venkateshwar G.
在上皮-间充质转化（EMT）期间，上皮癌细胞转分化成高度运动的、侵袭性的间充质样细胞，从而产生播散性肿瘤细胞。这些播散的细胞很少成功转移。肿瘤微环境中的免疫细胞和炎症被证明会驱动EMT，但很少有研究调查EMT对肿瘤免疫监视的后果。除了启动转移，我们证明EMT赋予增加的自然杀伤（NK）细胞的易感性，并有助于，在一定程度上，转移过程的效率低下。NK细胞的耗竭允许自发转移而不影响原发性肿瘤生长。EMT诱导的E-钙粘蛋白和细胞粘附分子1（CADM 1）的调节介导了对NK细胞毒性的易感性增加。在2个肺腺癌和1个乳腺癌患者队列中，较高的CADM 1表达与改善的患者存活率和降低的转移相关。我们的观察揭示了一种新的NK介导的肺癌转移特异性免疫监视，并通过提高NK细胞活性来预防转移。
During epithelial-mesenchymal transition (EMT) epithelial cancer cells transdifferentiate into highly motile, invasive, mesenchymal-like cells, giving rise to disseminating tumor cells. Few of these disseminated cells successfully metastasize. Immune cells and inflammation in the tumor microenvironment were shown to drive EMT, but few studies investigated the consequences of EMT for tumor immunosurveillance. In addition to initiating metastasis, we demonstrate that EMT confers increased susceptibility to natural killer (NK) cells and contributes, in part, to the inefficiency of the metastatic process. Depletion of NK cells allowed spontaneous metastasis without affecting primary tumor growth. EMT-induced modulation of E-cadherin and cell adhesion molecule 1 (CADM1) mediated increased susceptibility to NK cytotoxicity. Higher CADM1 expression correlates with improved patient survival in 2 lung and 1 breast adenocarcinoma patient cohorts and decreased metastasis. Our observations reveal a novel NK-mediated, metastasis-specific immunosurveillance in lung cancer and present a window of opportunity for preventing metastasis by boosting NK cell activity.