IL-9 Producing Tumor-Infiltrating Lymphocytes (Til) and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer

Although lung cancer is the leading cause of cancer death 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 lung pSTAT3, Th17 and 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 and induction of IL-21 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. Funding: This work was supported by DFG grant FI817-5-1,2 and by a DFG FI817- 5-3 granted to SF. M.T.C. work is supported by a DFG CH 1428/2-1. MHK was supported by NIH grant AI057459. Declaration of Interest: None to declare. Ethical Approval: Our human study was performed at the Friedrich-Alexander-University Erlangen-Nurnberg, Germany, after being approved by the ethics review board of the University of Erlangen (Re-No: 56_12B; DRKS-ID: DRKS00005376).