Esra A Akbay1, Shohei Koyama2, Yan Liu3, Ruben Dries3, Lauren E Bufe4, Michael Silkes4, Md Maksudul Alam1, Dillon M Magee1, Robert Jones5, Masahisa Jinushi6, Meghana Kulkarni4, Julian Carretero7, Xiaoen Wang3, Tiquella Warner-Hatten4, Jillian D Cavanaugh4, Akio Osa2, Atsushi Kumanogoh2, Gordon J Freeman3, Mark M Awad3, David C Christiani8, Raphael Bueno9, Peter S Hammerman3, Glenn Dranoff10, Kwok-Kin Wong11. 1. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Simmons Comprehensive Cancer Center, Dallas, Texas. 2. Department of Respiratory Medicine, Allergy, and Rheumatic Disease, Osaka University Graduate School of Medicine, Osaka, Japan. 3. Department of Medicine, Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 5. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. 6. Graduate School of Medicine, Institute for Advanced Medical Research, Keio University, Tokyo, Japan. 7. Department of Physiology, University of Valencia, Valencia, Spain. 8. Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 9. Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts. 10. Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. 11. Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. Electronic address: kwok-kin.wong@nyumc.org.
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.
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 patientlung 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:Krasmice. 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.
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