Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer
Peter J. Chockley, … , Theodore J. Standiford, Venkateshwar G. Keshamouni
Peter J. Chockley, … , Theodore J. Standiford, Venkateshwar G. Keshamouni
Published January 11, 2018
Citation Information: J Clin Invest. 2018;128(4):1384-1396. https://doi.org/10.1172/JCI97611.
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Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer

Abstract

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.

Authors

Peter J. Chockley, Jun Chen, Guoan Chen, David G. Beer, Theodore J. Standiford, Venkateshwar G. Keshamouni

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Figure 4

NKG2D receptor is not involved in EMT-induced susceptibility to NK-mediated cytotoxicity.

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NKG2D receptor is not involved in EMT-induced susceptibility to NK-media...
(A) NK92mi cells were transfected with 10 nM of scrambled (SCR) or NKG2D-specific siRNA. After 72 hours, NKG2D expression was assessed by Western immunoblotting (inset), and these cells were used as effectors against A549 cells that were treated with (EMT) or without (NON-EMT) TGF-β (5 ng/ml) for 72 hours in the NK cytotoxicity assay. (B) NKG2D receptors were neutralized by treatment of NK92mi cells with anti-NKG2D receptor antibody (50 μg/ml) 45 minutes before coculturing with EMT or non-EMT A549 cells in the NK cytotoxicity assay. Iso, isotype control. All experiments were repeated twice; representative data of 1 experiment are shown. Mean ± SEM is shown; 2-way ANOVA with Tukey’s post hoc analysis was performed, *P < 0.05, ***P < 0.001. For positive control K562 cytotoxicity, mean ± SEM is shown; 2-tailed, unpaired t tests were performed, *P < 0.05, ***P < 0.001.