Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade
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. We generated bitransgenic mice expressing a conditional IL-17A allele alo...
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Published in | Journal of thoracic oncology Vol. 12; no. 8; pp. 1268 - 1279 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
01.08.2017
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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.
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.
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Equal contribution |
ISSN: | 1556-0864 1556-1380 |
DOI: | 10.1016/j.jtho.2017.04.017 |