IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth

Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and an aberrant microbiota of the lung. Microbial colonization contributes to chronic neutrophilic inflammation in COPD. Nontypeable Haemophilus influenzae (NTHi) is frequently found in lungs of stable COPD patient and is the major pathogen triggering exacerbations. The epithelial cytokine IL-17C promotes the recruitment of neutrophils into inflamed tissues. The purpose of this study was to investigate the function of IL-17C in the pulmonary tumor microenvironment. We subjected mice deficient for IL-17C (IL-17C^-/-) and mice double deficient for Toll-like receptor 2 and 4 (TLR-2/4^-/-) to a metastatic lung cancer model. Tumor proliferation and growth as well as numbers of tumor-associated neutrophils were significantly decreased in IL-17C^-/- and TLR-2/4^-/- mice exposed to NTHi. The NTHi-induced pulmonary expression of IL-17C was dependent on TLR-2/4. In vitro, IL-17C increased the NTHi- and TNF-α-induced expression of the neutrophil chemokines keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 2 (MIP-2) in lung cancer cells but did not affect proliferation. Human lung cancer samples stained positive for IL-17C and in NSCLC patients with lymph node metastasis, IL-17C was identified as a negative prognostic factor. Our data indicate that epithelial IL-17C promotes neutrophilic inflammation in the tumor microenvironment and suggest that IL-17C links a pathologic microbiota, as present in COPD patients, with enhanced tumor growth.

No conflict of interest has been declared by the author(s).