Epithelial-to-mesenchymal transition hinders interferon-?-dependent immunosurveillance in lung cancer cells

The epithelial-to-mesenchymal transition (EMT) is involved in cancer metastasis; nevertheless, interferon (IFN)-gamma induces anticancer activities by causing cell growth suppression, cytotoxicity, and migration inhibition. Regarding the poor response to exogenously administered IFN-gamma as anticancer therapy, it was hypothesized that malignant cells may acquire a means of escaping from IFN-gamma immunosurveillance, likely through an EMT-related process. A genomic analysis of human lung cancers revealed a negative link between the EMT and IFN-gamma signaling, while compared to human lung adenocarcinoma A549 cells, IFN-gamma-hyporesponsive AS2 cells exhibited mesenchymal characteristics. Chemically, physically, and genetically engineered EMT attenuated IFN-gamma-induced IFN regulatory factor 1 transactivation. Poststimulation of transforming growth factor-beta induced the EMT and also selectively retarded IFN-gamma-responsive gene expression as well as IFN-gamma-induced signal transducer and activator of transcription 1 activation, major histocompatibility complex I, and CD54 expression, cell migration/ invasion inhibition, and direct/indirect cytotoxicity. Without changes in IFN-gamma receptors, excessive oxidative activation of Src homology-2 containing phosphatase 2 (SHP2) in cells undergoing the EMT primarily caused cellular hyporesponsiveness to IFN-gamma signaling and cytotoxicity, while combining an SHP2 inhibitor or antioxidant sensitized EMT-associated AS2 and mesenchymal A549 cells to IFN-gamma-induced priming effects on tumor necrosis factor-related apoptosis-inducing ligand cytotoxicity. In cell line-derived xenograft models, combined treatment with IFN-gamma and an SHP2 inhibitor induced enhanced anticancer activities. These results imply that EMT-associated SHP2 activation inhibits IFN-gamma signaling, facilitating lung cancer cell escape from IFN-gamma immunosurveillance.

Automated summary

The study reveals that tumor cells may escape from IFN-gamma immunosurveillance through EMT, and inhibiting SHP2 activation can enhance IFN-gamma-induced anticancer activities in lung cancer.