title: IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth.
abstract: 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 patients and is the major pathogen triggering exacerbations. The epithelial cytokine interleukin-17C (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 the number of tumor-associated neutrophils was 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 tumor necrosis factor-α-induced expression of the neutrophil chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 in lung cancer cells but did not affect proliferation. Human lung cancer samples stained positive for IL-17C, and in non-small cell lung cancer 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.
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Jungnickel
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pulmonology, University Hospital Münster, Münster, Germany.
authors.forename: L H
authors.initials: LH
authors.lastname: Schmidt
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bittigkoffer
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Ritzmann
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kamyschnikow
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Herr
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: M D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Gerhard-Domagk Institute of Pathology, University Hospital Muenster, Münster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Spieker
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pulmonology, University Hospital Münster, Münster, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wiewrodt
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Bals
authors.affiliation: Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Beisswenger
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: C515925:IL17C protein, human; C515930:Il17c protein, mouse; D020381:Interleukin-17; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4