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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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 6

Inhibition of CADM1 in tumor cells allows spontaneous metastasis without affecting primary tumor growth.

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Inhibition of CADM1 in tumor cells allows spontaneous metastasis without...
(A) mCherry-expressing CADM1 KO and control A549 cells were subcutaneously implanted into the dorsal flanks of RAG1–/– mice. Primary tumor growth was monitored, and mean tumor volumes are plotted; mean ± SEM shown. Data are representative of 1 experiment (n = 4–5 mice per group). (B) Overt lung nodules were counted on the excised lungs to assess spontaneous metastasis. Data represent 2 independent experiments, and pooled data are shown; error bars are SEM, and Mann-Whitney U test was performed, ****P < 0.0001. (C) Presence, or lack thereof, of metastatic spread was further confirmed by visualization of mCherry-positive tumor cells in the cross sections of the lungs by immunofluorescence. Top row scale bars: 500 μm; lower row: 50 μm, 100 μm, and 50μm, respectively.