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IL-17A and IL-17F orchestrate macrophages to promote lung cancer

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Abstract

Purpose

Previously, inflammation has been found to be associated with the development of lung cancer. Despite their well-characterized pro-inflammatory functions, the putative roles of interleukin-17 (IL-17) cytokine family members in tumorigenesis have remained controversial. While IL-17A exhibits both pro- and anti-tumor effects, IL-17F has been suggested to serve as a candidate for cancer therapy. Thus, we aimed at clarifying the involvement of IL-17A/F in lung cancer.

Methods

IL-17 receptor expression in human and murine lung cancer cells was assessed using immunofluorescence. The effect of IL-17A/F stimulation on lung cancer cell viability (SRB assay) and metabolism (glucose consumption and lactate production) was evaluated under normoxic and hypoxic conditions. Characterization of IL-17A/F-stimulated macrophages was performed by flow cytometry and ELISA. The effect of conditioned media (CM) from IL-17A/F-stimulated macrophages was evaluated on lung cancer cell migration. The effect of CM-stimulated macrophages on lung tumor growth, proliferation and angiogenesis was evaluated in vivo using a chicken chorioallantoic membrane (CAM) assay.

Results

No alterations in lung cancer cell viability or metabolism were observed upon direct stimulation with IL-17A/F. We found, however, that CM from IL-17A/F-stimulated macrophages promoted both murine and human lung cancer cell progression through an increased migration capacity in vitro and enhanced in vivo tumor growth, proliferation and angiogenesis. These findings were supported by an increased polarization of human macrophages towards a M2-like phenotype.

Conclusions

Our data indicate that IL-17A/F act through immune cell orchestration, i.e., of macrophages, to promote lung cancer cell growth and progression. In addition, our data provide a link between IL-17A/F activity and lung cancer cell-macrophage crosstalk.

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Acknowledgements

This work was carried out under the scope of the project NORTE-01-0145-FEDER- 000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal Partnership Agreement, through the European Regional Development Fund (FEDER), and through the Competitiveness Factors Operational Programme (COMPETE) and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. SG and IM received fellowships from FCT, ref. SFRH/BPD/117858/2016, and SFRH/BD/120127/2016 respectively. RS received a contract from FCT ref. IF/00021/2014.

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  1. Ricardo Silvestre and Sara Granja are authorship of equal contribution

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Nathalia Ferreira, Inês Mesquita, Fátima Baltazar, Ricardo Silvestre & Sara Granja

  2. ICVS/3B’s–PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Nathalia Ferreira, Inês Mesquita, Fátima Baltazar, Ricardo Silvestre & Sara Granja

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Ferreira, N., Mesquita, I., Baltazar, F. et al. IL-17A and IL-17F orchestrate macrophages to promote lung cancer. Cell Oncol. 43, 643–654 (2020). https://doi.org/10.1007/s13402-020-00510-y

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