Chockley et al. demonstrate in vitro and in vivo that during the epithelial-mesenchymal transition and associated metastasis, tumor cells become increasingly susceptible to NK cell killing due to increased expression of cell adhesion molecule 1 (CADM1, an activating NK ligand) and decreased expression of E-cadherin (an inhibitory NK ligand). Higher CADM1 expression correlated with improved patient survival and lower rate of metastasis, suggesting that boosting NK cell activity may be a therapeutic target that could help to prevent metastasis formation.
During epithelial-mesenchymal transition (EMT) epithelial cancer cells trans-differentiate into highly-motile, invasive, mesenchymal-like cells giving rise to disseminating tumor cells. Only few of these disseminated cells successfully metastasize. Immune cells and inflammation in the tumor microenvironment was shown to drive EMT, but few studies investigated the consequences of EMT on tumor immunosurveillance. In addition to initiating metastasis, we demonstrate that EMT confers increased susceptibility to NK cells and contributes, in part, to the inefficiency of the metastatic process. Depletion of NK cells allowed spontaneous metastasis without effecting 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 two lung and one breast adenocarcinoma patient cohorts and decreased metastasis. Our observation reveal a novel NK-mediated, metastasis-specific, immunosurveillance in lung cancer and presents a window of opportunity for the prevention of metastasis by boosting NK cell activity.