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.

IL‐17C amplifies epithelial inflammation in human psoriasis and atopic eczema

“…In vitro stimulation of keratinocytes with IL‐17C was sufficient to induce neutrophil migration via CXCL8. This observation is in concordance with a report linking IL‐17C to the recruitment of neutrophils in lung cancer . Of note, IL‐17C induced chemokines of Th1 (CXCL10), Th2 (CCL5) and Th17 immunity (CXCL8), thus pointing out that IL‐17C is not exclusively related to one specific type of T cell‐mediated inflammation.…”

IL-17C/IL-17RE: Emergence of a Unique Axis in TH17 Biology

“…Further diseases involving the IL-17C/RE axis include psoriasiform skin lesions in inflammatory bowel disease (IBD) patients under anti-TNF-α treatment (53), recurrent aphthous ulcers (20), LPS-induced endotoxin shock (52), and different forms of cancer (38,(54)(55)(56) (Tables 2, 3).…”

Interleukin 17 Receptor E (IL-17RE) and IL-17C Mediate the Recruitment of Neutrophils during Acute Streptococcus pneumoniae Pneumonia

“…Moreover, administration of adenoviruses expressing IL-17C and application of recombinant IL-17C result in the recruitment of neutrophils into the lung (15,16). We have shown that IL-17C promotes neutrophilic lung inflammation during acute Pseudomonas aeruginosa pneumonia and inflammationinduced recruitment of neutrophils into the microenvironment of lung tumors (6,17,18).…”