Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade

Esra A. Akbay, Shohei Koyama, Yan Liu, Ruben Dries, Lauren E. Bufe, Michael Silkes, MD Maksudul Alam, Dillon M. Magee, Robert Jones, Masahisa Jinushi, Meghana Kulkarni, Julian Carretero, Xiaoen Wang, Tiquella Warner-Hatten, Jillian D. Cavanaugh, Akio Osa, Atsushi Kumanogoh, Gordon J. Freeman, Mark M. Awad, David C. ChristianiRaphael Bueno, Peter S. Hammerman, Glenn Dranoff, Kwok Kin Wong

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Introduction Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses. Methods We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD-1) or IL-6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors. Results Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared with that of KrasG12D mice. IL-6, granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein, and C-X-C motif chemokine ligand 1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that levels of tumor-associated neutrophils were significantly increased, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared with in KrasG12D mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti–Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T-cell activation. In tumors from patients with lung cancer with KRAS mutation we found a correlation between higher levels of IL-17A and colony- stimulating factor 3 and a significant correlation among high neutrophil and lower T-cell numbers. Conclusions Here we have shown that an increase in a single cytokine, IL-17A, without additional mutations can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine and neutrophil depletion.

Original languageEnglish (US)
Pages (from-to)1268-1279
Number of pages12
JournalJournal of Thoracic Oncology
Volume12
Issue number8
DOIs
StatePublished - Aug 2017

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Keywords

  • Cytokines
  • IL-17
  • MDSC
  • Neutrophils
  • PD-1
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Akbay, E. A., Koyama, S., Liu, Y., Dries, R., Bufe, L. E., Silkes, M., Alam, MD. M., Magee, D. M., Jones, R., Jinushi, M., Kulkarni, M., Carretero, J., Wang, X., Warner-Hatten, T., Cavanaugh, J. D., Osa, A., Kumanogoh, A., Freeman, G. J., Awad, M. M., ... Wong, K. K. (2017). Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade. Journal of Thoracic Oncology, 12(8), 1268-1279. https://doi.org/10.1016/j.jtho.2017.04.017