AI Article Synopsis
- IL-17A is found to be overexpressed in some lung cancer patients and may encourage tumor growth by enhancing inflammation and suppressing immune responses.
- Researchers conducted experiments using genetically modified mice to study the effects of IL-17A on lung tumors, finding faster tumor growth and poorer survival rates compared to normal controls.
- Treatment with antibodies that block IL-6 or deplete neutrophils improved outcomes in IL-17A-expressing tumors, indicating a potential therapeutic strategy for patients with this cytokine's elevation.
Article 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 Kras 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 mice grew more rapidly, resulting in a significantly shorter survival as compared with that of Kras 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:Kras mice as compared with in Kras mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:Kras tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:Kras 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532066 | PMC |
| http://dx.doi.org/10.1016/j.jtho.2017.04.017 | DOI Listing |
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