Heim, LisanneYang, ZuqinTausche, PatrickHohenberger, KatjaChiriac, Mircea T.Koelle, JuliaGeppert, Carol-ImmanuelKachler, KaterinaMiksch, SarahGraser, AnnaFriedrich, JulianeKharwadkar, RakshinRieker, Ralf J.Trufa, Denis I.Sirbu, HoriaNeurath, Markus F.Kaplan, Mark H.Finotto, Susetta2023-06-222023-06-222022-04-20Heim L, Yang Z, Tausche P, et al. IL-9 Producing Tumor-Infiltrating Lymphocytes and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer. Front Immunol. 2022;13:859738. Published 2022 Apr 20. doi:10.3389/fimmu.2022.859738https://hdl.handle.net/1805/33924Although lung cancer is the leading cause of cancer deaths worldwide, the mechanisms how lung cancer cells evade the immune system remain incompletely understood. Here, we discovered IL-9-dependent signaling mechanisms that drive immune evasion in non-small cell lung cancer (NSCLC). We found increased IL-9 and IL-21 production by T cells in the tumoral region of the lung of patients with NSCLC, suggesting the presence of Th9 cells in the lung tumor microenvironment. Moreover, we noted IL-9 producing Tregs in NSCLC. IL-9 target cells in NSCLC consisted of IL-9R+ tumor cells and tumor-infiltrating lymphocytes. In two murine experimental models of NSCLC, and in vitro, IL-9 prevented cell death and controlled growth of lung adenocarcinoma cells. Targeted deletion of IL-9 resulted in successful lung tumor rejection in vivo associated with an induction of IL-21 and reduction of Treg cells. Finally, anti-IL-9 antibody immunotherapy resulted in suppression of tumor development even in established experimental NSCLC and was associated with reduced IL-10 production in the lung. In conclusion, our findings indicate that IL-9 drives immune escape of lung tumor cells via effects on tumor cell survival and tumor infiltrating T cells. Thus, strategies blocking IL-9 emerge as a new approach for clinical therapy of lung cancer.en-USAttribution 4.0 InternationalImmune escapeTumor immunotherapyLung neoplasmsInterleukin-9Non-small cell lung cancerArticle