TGF-β protects dormant metastasis from immune mechanosurveillance

Cancer cells disseminated to distant sites enter a period of dormancy before generating overt metastases. The ability of these cells to elude immune surveillance determines their persistence as latent disease. We report that TGF-β promotes dormancy in lung adenocarcinoma (LUAD) mouse models by placing disseminated SOX2+ and NKX2-1+ progenitors in a quiescent state that biomechanically averts killing by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In these primitive progenitors, TGF-β induces an atypical epithelial-to-mesenchymal transition (EMT) lacking actin stress fibers. TGF-β drives expression of the actin-depolymerizing factor gelsolin that changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the stiffness of metastatic progenitors and their killing by mechanosensitive CTLs and NK cells. Thus, LUAD primitive progenitors activate a biomechanical process to evade immune-mediated elimination during prolonged dormancy periods. Inhibiting this process clears tissues of dormant metastatic cells.