Differentiation and Immune Regulation of IL-9-Producing CD4+ T Cells in Malignant Pleural Effusion

Rationale: IL-9 producing CD4(+) T cells (Th9 cells) have been reported to be involved in inflammation and immune diseases. However, the involvement of Th9 cells in malignancy has not been investigated. Objectives: To elucidate the mechanism by which Th9 cells differentiate in malignant pleural effusion (MPE) and to explore the immune regulation of Th9 cells on lung cancer cells. Methods: Distribution of Th9 cells in relation to Th17 and Th1 cells in both MPE and blood were determined. The effects and mechanisms of proinflammatory cytokines and regulatory T cells on differentiation of Th9 cells in vitro were explored. The impacts and signal transductions of IL-9, IL-17, and IFN-gamma on lung cancer cell lines were also investigated. Measurements and Main Results: The numbers of Th9, Th17, and Th1 cells were all increased in M PE when compared with blood. The increase in Th9 cells in MPE was due to the promotion by cytokines and regulatory T cells. By activating STAT3 signaling, both IL-9 and IL-17 substantially promoted the proliferation and migratory activity of lung cancer cells, whereas IFN-gamma, which activated STAT1 signaling, was noted to suppress lung cancer cell proliferation and migration. IFN-gamma could induce lung cancer cell apoptosis. Moreover, IL-9 and IFN-gamma, but not IL-17, could strongly facilitate intercellular adhesion of lung cancer cells to pleural mesothelial cell monolayers. Conclusions: Our data revealed that Th9 cells were increased in MPE and that Th9 cells exerted an important immune regulation on lung cancer cells in human tumor environment.