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

Oncogene volume 36, pages 4182–4190 (2017)Cite this article

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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.

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References

  1. Adcock IM, Caramori G, Barnes PJ . Chronic obstructive pulmonary disease and lung cancer: new molecular insights. Respiration 2011; 81: 265–284.

    Article  CAS  PubMed  Google Scholar 

  2. Young RP, Hopkins RJ, Christmas T, Black PN, Metcalf P, Gamble GD . COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009; 34: 380–386.

    Article  CAS  PubMed  Google Scholar 

  3. Zulueta JJ, Wisnivesky JP, Henschke CI, Yip R, Farooqi AO, McCauley DI et al. Emphysema scores predict death from COPD and lung cancer. Chest 2012; 141: 1216–1223.

    Article  PubMed  Google Scholar 

  4. Hoenderdos K, Condliffe A . The neutrophil in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2013; 48: 531–539.

    Article  CAS  PubMed  Google Scholar 

  5. Roos AB, Sethi S, Nikota J, Wrona CT, Dorrington MG, Sanden C et al. IL-17 A and the promotion of neutrophilia in acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 192: 428–437.

    Article  CAS  PubMed  Google Scholar 

  6. Sethi S . Infection as a comorbidity of COPD. Eur Respir J 2010; 35: 1209–1215.

    Article  CAS  PubMed  Google Scholar 

  7. Grivennikov SI, Greten FR, Karin M . Immunity, inflammation, and cancer. Cell 2010; 140: 883–899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 2009; 457: 102–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li D, Beisswenger C, Herr C, Hellberg J, Han G, Zakharkina T et al. Myeloid cell RelA/p65 promotes lung cancer proliferation through Wnt/beta-catenin signaling in murine and human tumor cells. Oncogene 2013; 33: 1239–1248.

    Article  PubMed  Google Scholar 

  10. Li D, Beisswenger C, Herr C, Schmid RM, Gallo RL, Han G et al. Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth. Oncogene 2013; 33: 2709–2716.

    Article  PubMed  Google Scholar 

  11. Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M . Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 2010; 17: 89–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci USA 2014; 111: 5664–5669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jungnickel C, Wonnenberg B, Karabiber O, Wolf A, Voss M, Wolf L et al. Cigarette smoke induced disruption of pulmonary barrier and bacterial translocation drive tumor associated inflammation and growth. Am J Physiol Lung Cell Mol Physiol 2015; 309: L605–L613; ajplung 00116 02015.

    Article  CAS  PubMed  Google Scholar 

  14. Moghaddam SJ, Li H, Cho SN, Dishop MK, Wistuba II, Ji L et al. Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. Am J Respir Cell Mol Biol 2009; 40: 443–453.

    Article  CAS  PubMed  Google Scholar 

  15. Kusagaya H, Fujisawa T, Yamanaka K, Mori K, Hashimoto D, Enomoto N et al. Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner. Am J Respir Cell Mol Biol 2014; 50: 30–39.

    CAS  PubMed  Google Scholar 

  16. Pfeifer P, Voss M, Wonnenberg B, Hellberg J, Seiler F, Lepper PM et al. IL-17C is a mediator of respiratory epithelial innate immune response. Am J Respir Cell Mol Biol 2013; 48: 415–421.

    Article  CAS  PubMed  Google Scholar 

  17. Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol 2011; 12: 1159–1166.

    Article  CAS  PubMed  Google Scholar 

  18. Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD et al. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol 2011; 12: 1151–1158.

    Article  CAS  PubMed  Google Scholar 

  19. Wolf L, Sapich S, Honecker A, Jungnickel C, Seiler F, Bischoff M et al. IL-17 A-mediated expression of epithelial IL-17C promotes inflammation during acute Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 2016; 311: L1015–L1022.

    Article  PubMed  Google Scholar 

  20. Johansen C, Riis JL, Gedebjerg A, Kragballe K, Iversen L . Tumor necrosis factor alpha-mediated induction of interleukin 17C in human keratinocytes is controlled by nuclear factor kappaB. J Biol Chem 2011; 286: 25487–25494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gaffen SL . Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 2009; 9: 556–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 2002; 169: 443–453.

    Article  CAS  PubMed  Google Scholar 

  23. Li D, Beisswenger C, Herr C, Schmid RM, Gallo RL, Han G et al. Expression of the antimicrobial peptide cathelicidin in myeloid cells is required for lung tumor growth. Oncogene 2014; 33: 2709–2716.

    Article  CAS  PubMed  Google Scholar 

  24. Voss M, Wolf L, Kamyschnikow A, Wonnenberg B, Honecker A, Herr C et al. IL-17A contributes to maintenance of pulmonary homeostasis in a murine model of cigarette smoke-induced emphysema. Am J Physiol Lung Cell Mol Physiol 2015; 309: L188–L195.

    Article  CAS  PubMed  Google Scholar 

  25. Li D, Beisswenger C, Herr C, Hellberg J, Han G, Zakharkina T et al. Myeloid cell RelA/p65 promotes lung cancer proliferation through Wnt/beta-catenin signaling in murine and human tumor cells. Oncogene 2014; 33: 1239–1248.

    Article  PubMed  Google Scholar 

  26. Pfeifer P, Voss M, Wonnenberg B, Hellberg J, Seiler F, Lepper PM et al. IL-17C is a mediator of respiratory epithelial innate immune response. Am J Respir Cell Mol Biol 2012; 48: 415–421.

    Article  Google Scholar 

  27. Marsland BJ, Gollwitzer ES . Host–microorganism interactions in lung diseases. Nat Rev Immunol 2014; 14: 827–835.

    Article  CAS  PubMed  Google Scholar 

  28. Yadava K, Pattaroni C, Sichelstiel AK, Trompette A, Gollwitzer ES, Salami O et al. Microbiota promotes chronic pulmonary inflammation by enhancing IL-17 A and autoantibodies. Am J Respir Crit Care Med 2016; 193: 975–987.

    Article  CAS  PubMed  Google Scholar 

  29. Karin M, Greten FR . NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749–759.

    Article  CAS  PubMed  Google Scholar 

  30. Papi A, Casoni G, Caramori G, Guzzinati I, Boschetto P, Ravenna F et al. COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma. Thorax 2004; 59: 679–681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Friedrich M, Diegelmann J, Schauber J, Auernhammer CJ, Brand S . Intestinal neuroendocrine cells and goblet cells are mediators of IL-17 A-amplified epithelial IL-17C production in human inflammatory bowel disease. Mucosal Immunol 2015; 8: 943–958.

    Article  CAS  PubMed  Google Scholar 

  32. Bellocq A, Antoine M, Flahault A, Philippe C, Crestani B, Bernaudin JF et al. Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol 1998; 152: 83–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Teramukai S, Kitano T, Kishida Y, Kawahara M, Kubota K, Komuta K et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer 2009; 45: 1950–1958.

    Article  PubMed  Google Scholar 

  34. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 2015; 522: 345–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. El Rayes T, Catena R, Lee S, Stawowczyk M, Joshi N, Fischbach C et al. Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1. Proc Natl Acad Sci USA 2015; 112: 16000–16005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci USA 2010; 107: 21248–21255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wculek SK, Malanchi I . Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 2015; 528: 413–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 2010; 16: 219–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hattar K, Savai R, Subtil FS, Wilhelm J, Schmall A, Lang DS et al. Endotoxin induces proliferation of NSCLC in vitro and in vivo: role of COX-2 and EGFR activation. Cancer Immunol Immunother 2013; 62: 309–320.

    Article  CAS  PubMed  Google Scholar 

  40. Song X, Gao H, Lin Y, Yao Y, Zhu S, Wang J et al. Alterations in the microbiota drive interleukin-17C production from intestinal epithelial cells to promote tumorigenesis. Immunity 2014; 40: 140–152.

    Article  CAS  PubMed  Google Scholar 

  41. Klein M, Obermaier B, Angele B, Pfister HW, Wagner H, Koedel U et al. Innate immunity to pneumococcal infection of the central nervous system depends on toll-like receptor (TLR) 2 and TLR4. J Infect Dis 2008; 198: 1028–1036.

    Article  CAS  PubMed  Google Scholar 

  42. Koedel U, Merbt UM, Schmidt C, Angele B, Popp B, Wagner H et al. Acute brain injury triggers MyD88-dependent, TLR2/4-independent inflammatory responses. Am J Pathol 2007; 171: 200–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rad R, Ballhorn W, Voland P, Eisenacher K, Mages J, Rad L et al. Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 2009; 136: 2247–2257.

    Article  CAS  PubMed  Google Scholar 

  44. Herr C, Han G, Li D, Tschernig T, Dinh QT, Beisswenger C et al. Combined exposure to bacteria and cigarette smoke resembles characteristic phenotypes of human COPD in a murine disease model. Exp Toxicol Pathol 2015; 67: 261–269.

    Article  CAS  PubMed  Google Scholar 

  45. Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C . Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity 2011; 35: 611–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pfaffl MW . A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Res 2001; 29: e45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Remmele W, Stegner HE . Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 1987; 8: 138–140.

    CAS  PubMed  Google Scholar 

  48. Schmidt LH, Gorlich D, Spieker T, Rohde C, Schuler M, Mohr M et al. Prognostic impact of Bcl-2 depends on tumor histology and expression of MALAT-1 lncRNA in non-small-cell lung cancer. J Thorac Oncol 2014; 9: 1294–1304.

    Article  CAS  PubMed  Google Scholar 

  49. Hess C, Herr C, Beisswenger C, Zakharkina T, Schmid RM, Bals R . Myeloid RelA regulates pulmonary host defense networks. Eur Respir J 2010; 35: 343–352.

    Article  CAS  PubMed  Google Scholar 

  50. Gyorffy B, Surowiak P, Budczies J, Lanczky A . Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One 2013; 8: e82241.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Anja Honecker for excellent technical assistance. This study was supported by grants from the Wilhelm-Sander-Stiftung to Christoph Beisswenger and Robert Bals.

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Authors and Affiliations

  1. Department of Internal Medicine V—Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg/Saar, Germany

    C Jungnickel, L Bittigkoffer, L Wolf, A Wolf, F Ritzmann, A Kamyschnikow, C Herr, R Bals & C Beisswenger

  2. Department of Medicine A, Hematology, Oncology and Pulmonology, University Hospital Münster, Münster, Germany

    L H Schmidt & R Wiewrodt

  3. Institute for Clinical and Experimental Surgery, Saarland University Medical Center, Homburg/Saar, Germany

    M D Menger

  4. Gerhard-Domagk Institute of Pathology, University Hospital Muenster, Münster, Germany

    T Spieker

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Jungnickel, C., Schmidt, L., Bittigkoffer, L. et al. IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth. Oncogene 36, 4182–4190 (2017). https://doi.org/10.1038/onc.2017.28

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