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 2

NK cell depletion allows spontaneous metastatic spread without affecting primary tumor growth.

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NK cell depletion allows spontaneous metastatic spread without affecting...
(A–F) To assess the effect of NK cell depletion on primary tumor growth and metastasis, indicated cell lines were implanted subcutaneously under the dorsal flanks of RAG1–/– or C57BL/6 mice. Mice were treated weekly with anti–asialo GM1 antibody (ASGM1) to deplete NK cells or with normal rabbit serum (NRS) as control. (A, C, and E) Primary tumor growth was monitored, and mean tumor volumes are plotted with error bars as SEM. Representative data from a single experiment of at least duplicates. (B, D, and F) Overt lung nodules were counted on the excised lungs to assess spontaneous metastasis. Mouse strains and tumor cell implants are designated. Error bars are SEM; Mann-Whitney U test was performed, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data represent at least 2 experiments, n = 4–5 per group, and pooled data are shown.