Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer
Peter J. Chockley, Jun Chen, Guoan Chen, David G. Beer, Theodore J. Standiford, Venkateshwar G. Keshamouni
Peter J. Chockley, Jun Chen, Guoan Chen, David G. Beer, Theodore J. Standiford, Venkateshwar G. Keshamouni
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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 8

Reduced CADM1 expression is correlated to worse patient survival and metastasis.

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Reduced CADM1 expression is correlated to worse patient survival and met...
(A) The lung adenocarcinoma patient cohort of Shedden et al. (41) (Lung n = 442) was stratified into groups expressing low and high CADM1 and was assessed for overall survival. (B and C) The Shedden et al. data set is further classified into subgroups based on tumor stage and nodal status recorded at the time of diagnosis. Mean CADM1 expression and its distribution are depicted in the violin plots with box-and-whisker overlays in white. Two-tailed, unpaired t tests were performed, *P < 0.05; **P < 0.01. (D) The lung adenocarcinoma patient cohort of Györffy et al. (42) (Lung n = 720) was stratified into groups expressing low and high CADM1 and was assessed for overall survival. (E) The breast carcinoma patient cohort of Györffy et al. (43) [estrogen receptor–positive (ER+) breast n = 548] was stratified into groups expressing low and high CADM1 and was assessed for overall survival. (A, D, and E) Data sets shown here are Kaplan-Meier survival curves with log-rank P values comparing the groups.