Epithelial-to-mesenchymal transition hinders interferon-γ-dependent immunosurveillance in lung cancer cells. (28th July 2022)

• Record Type: Journal Article
• Authors: Tseng, Po-Chun; Chen, Chia-Ling; Lee, Kang-Yuan; Feng, Po-Hao; Wang, Yu-Chih; Satria, Rahmat Dani; Lin, Chiou-Feng
• Is Part Of: Cancer letters. Volume 539(2022)
• Publication Date: 2022-07-28
• Subjects: EMT -- IFN-γ -- STAT1 -- MHC -- Cytotoxicity; EMT Epithelial-to-mesenchymal transition -- Ep-CAM Epithelial cell adhesion molecule -- IFN-γ Interferon-γ -- JAK Janus kinase -- SHP Src homology-2 containing phosphatase -- STAT Signal transducer and activator of transcription -- TGF Transforming growth factor -- VIM Vimentin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215712
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The epithelial-to-mesenchymal transition (EMT) is involved in cancer metastasis; nevertheless, interferon (IFN)-γ induces anticancer activities by causing cell growth suppression, cytotoxicity, and migration inhibition. Regarding the poor response to exogenously administered IFN-γ as anticancer therapy, it was hypothesized that malignant cells may acquire a means of escaping from IFN-γ immunosurveillance, likely through an EMT-related process. A genomic analysis of human lung cancers revealed a negative link between the EMT and IFN-γ signaling, while compared to human lung adenocarcinoma A549 cells, IFN-γ-hyporesponsive AS2 cells exhibited mesenchymal characteristics. Chemically, physically, and genetically engineered EMT attenuated IFN-γ-induced IFN regulatory factor 1 transactivation. Poststimulation of transforming growth factor-β induced the EMT and also selectively retarded IFN-γ-responsive gene expression as well as IFN-γ-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-γ receptors, excessive oxidative activation of Src homology-2 containing phosphatase 2 (SHP2) in cells undergoing the EMT primarily caused cellular hyporesponsiveness to IFN-γ signaling and cytotoxicity, while combining an SHP2 inhibitor or antioxidant sensitized EMT-associated AS2 and mesenchymal A549 cells to IFN-γ-induced priming effects on tumor necrosis factor-related apoptosis-inducing ligand cytotoxicity. In cell line-derived xenograft models, combined treatment with IFN-γ and an SHP2 inhibitor induced enhanced anticancer activities. These results imply that EMT-associated SHP2 activation inhibits IFN-γ signaling, facilitating lung cancer cell escape from IFN-γ immunosurveillance. Highlights: The malignant lung cancer cells acquire EMT to escape from IFN-γ immunosurveillance. SHP2 in EMT cells determine cellular hyporesponsiveness to IFN-γ signaling and cytotoxicity. Combined treatment with IFN-γ and an SHP2 inhibitor induced enhances anticancer therapy in vitro and in vivo.