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

被引:168
作者
Akbay, Esra A. [1 ,2 ]
Koyama, Shohei [3 ]
Liu, Yan [4 ,5 ]
Dries, Ruben [5 ]
Bufe, Lauren E. [5 ]
Silkes, Michael [5 ]
Alath, M. D. Maksudul [1 ,2 ]
Magee, Dillon M. [1 ,2 ]
Jones, Robert [6 ]
Jinushi, Masahisa [7 ]
Kulkarni, Meghana [5 ]
Carretero, Julian [8 ]
Wang, Xiaoen [4 ,5 ]
Warner-Hatten, Tiquella [5 ]
Cavanaugh, Jillian D. [5 ]
Osa, Akio [3 ]
Kumanogoh, Atsushi [3 ]
Freeman, Gordon J. [4 ,5 ]
Awad, Mark M. [4 ,5 ]
Christiani, David C. [9 ]
Bueno, Raphael [10 ]
Hammerman, Peter S. [4 ,5 ]
Dranoff, Glenn [11 ]
Wong, Kwok-Kin [12 ]
机构
[1] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX USA
[2] Simmons Comprehens Canc Ctr, Dallas, TX USA
[3] Osaka Univ, Grad Sch Med, Dept Resp Med Allergy & Rheumat Dis, Osaka, Japan
[4] Harvard Med Sch, Dept Med, Boston, MA USA
[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[6] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA
[7] Keio Univ, Inst Adv Med Res, Grad Sch Med, Tokyo, Japan
[8] Univ Valencia, Dept Physiol, Valencia, Spain
[9] Harvard TH Chan Sch Publ Hlth, Boston, MA USA
[10] Brigham & Womens Hosp, Thorac Surg, 75 Francis St, Boston, MA 02115 USA
[11] Novartis Inst Biomed Res, Cambridge, MA USA
[12] NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, New York, NY USA
基金
美国国家卫生研究院;
关键词
Cytokines; IL-17; Neutrophils; MDSC; PD-1; Resistance; DELTA T-CELLS; MOUSE MODEL; PROGNOSTIC MARKER; LYMPHOCYTE RATIO; KRAS MUTATIONS; CANCER; EGFR; ACTIVATION; ADENOCARCINOMA; INFLAMMATION;
D O I
10.1016/j.jtho.2017.04.017
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Introduction: Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a pro-tumorigenic inflammatory phenotype and inhibits antitumor immune responses. Methods: We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional Kras(G12D) 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:Kras(G12D) 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 Kras(Gl2D) mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:Kras(G12D) tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:Kras(G12D) 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. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
引用
收藏
页码:1268 / 1279
页数:12
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