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 April 2, 2018; First published January 11, 2018
Citation Information: J Clin Invest. 2018;128(4):1384-1396. https://doi.org/10.1172/JCI97611.
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Categories: Research Article Immunology Oncology

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 3

Loss of E-cad expression sensitizes tumor cells to NK-mediated cytotoxicity through KLRG1.

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Loss of E-cad expression sensitizes tumor cells to NK-mediated cytotoxic...
(A) A549 cells were transfected with 10 nM of scrambled (SCR) or 3 different E-cad–specific siRNA molecules. After 24 hours, cells were treated with (EMT) or without (NON-EMT) TGF-β (5 ng/ml) for 72 hours. E-cad and GAPDH expressions were assessed by Western immunoblotting. (B) Susceptibility to NK cytotoxicity was assessed using NK92mi cells as effectors, as described for Figure 1. Mean ± SEM is shown; 1-way ANOVA with Tukey’s post hoc analysis was performed, **P < 0.01, ****P < 0.0001. (C) NK92mi cells were transfected with 10 nM of SCR or KLRG1-specific siRNA. After 72 hours, KLRG1 expression was assessed by flow cytometry. gMFI, geometric mean fluorescence intensity. (D) NK92mi cells from C were used as effectors against EMT or non-EMT A549 cells in the NK cytotoxicity assay. Mean ± SEM is shown; 2-way ANOVA with Tukey’s post hoc analysis was performed, **P < 0.01, ****P < 0.0001. All experiments were repeated twice, and data are representative of 1 experiment.