@article{2a1259f3b1094f48a4f6ffeddacc44e9,
title = "Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade",
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.",
keywords = "Cytokines, IL-17, MDSC, Neutrophils, PD-1, Resistance",
author = "Akbay, {Esra A.} and Shohei Koyama and Yan Liu and Ruben Dries and Bufe, {Lauren E.} and Michael Silkes and Alam, {MD Maksudul} and Magee, {Dillon M.} and Robert Jones and Masahisa Jinushi and Meghana Kulkarni and Julian Carretero and Xiaoen Wang and Tiquella Warner-Hatten and Cavanaugh, {Jillian D.} and Akio Osa and Atsushi Kumanogoh and Freeman, {Gordon J.} and Awad, {Mark M.} and Christiani, {David C.} and Raphael Bueno and Hammerman, {Peter S.} and Glenn Dranoff and Wong, {Kwok Kin}",
note = "Funding Information: This work was supported by National Institutes of Health/National Cancer Institute grants P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10, and 5R01CA166480-04 to Dr. Wong. Dr. Akbay is supported by the International Association for the Study of Lung Cancer Young Investigator Award and Cancer Prevention and Research Institute of Texas Scholar Award RR160080. Dr. Koyama is supported by the Project for Cancer Research and Therapeutic Evolution of the Japan Agency for Medical Research and Development and research grants from Mochida Foundation, the Astellas Foundation, the Suzuken Memorial Foundation and JSPS Kakenhi. Dr. Hammerman is supported by the Damon Runyon Cancer Research Foundation, Starr Consortium for Cancer Research, and National Cancer Institute grant R01 CA 205150. Dr. Freeman is supported by P50CA101942. In addition, Drs. Hammerman and K.K. Wong are supported by a Stand Up To Cancer?American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant no. SU2CAACR-DT17-15). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. We thank the Harvard Medical School Rodent Pathology Core and Rod Bronson for tissue processing, Mei Zhang for immunohistochemistry, the Dana-Farber Flow Cytometry Core for help with flow cytometry, Kristen Labbe and Christina Almonte for administrative support, and Daryl Harmon for reading and editing the manuscript. Funding Information: This work was supported by National Institutes of Health/National Cancer Institute grants P01 CA120964 , 5R01CA163896-04 , 1R01CA195740-01 , 5R01CA140594-07 , 5R01CA122794-10 , and 5R01CA166480-04 to Dr. Wong. Dr. Akbay is supported by the International Association for the Study of Lung Cancer Young Investigator Award and Cancer Prevention and Research Institute of Texas Scholar Award RR160080. Dr. Koyama is supported by the Project for Cancer Research and Therapeutic Evolution of the Japan Agency for Medical Research and Development and research grants from Mochida Foundation, the Astellas Foundation, the Suzuken Memorial Foundation and JSPS Kakenhi. Dr. Hammerman is supported by the Damon Runyon Cancer Research Foundation, Starr Consortium for Cancer Research, and National Cancer Institute grant R01 CA 205150 . Dr. Freeman is supported by P50CA101942. In addition, Drs. Hammerman and K.K. Wong are supported by a Stand Up To Cancer–American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant no. SU2CAACR-DT17-15). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. We thank the Harvard Medical School Rodent Pathology Core and Rod Bronson for tissue processing, Mei Zhang for immunohistochemistry, the Dana-Farber Flow Cytometry Core for help with flow cytometry, Kristen Labbe and Christina Almonte for administrative support, and Daryl Harmon for reading and editing the manuscript. Publisher Copyright: {\textcopyright} 2017 International Association for the Study of Lung Cancer",
year = "2017",
month = aug,
doi = "10.1016/j.jtho.2017.04.017",
language = "English (US)",
volume = "12",
pages = "1268--1279",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "8",
}