Aims and objectives: We hypothesized that the proinflammatory cytokine interleukin(IL)-17A and its receptor IL-17 receptor C (IL-17RC) modulates tumor progression in lung tumor microenvironment and associated with poor prognosis. We aim to investigate the pathophysiological role and impact of IL-17A in lung adenocarcinoma (LUAD) with different epidermal growth factor receptor (EGFR) mutation statuses.

Methods: The associations between IL-17A/IL-17RC axis and LUAD were investigated using the TGCA and GSE databases. With the presence or absence of IL-17A, cell proliferation, EGFR signaling, EGFR-tyrosine kinase inhibitor (TKI) resistance assay, EGFR trafficking or degradation were examined in LUAD cell lines with different EGFR statuses. 

Results: Upregulated IL-17A and IL-17RC expressions predicts poor survival in the LUAD patient cohorts. IL-17A promotes LUAD cell proliferation by activation of EGFR. IL-17A concurrently enhances EGFR and Met phosphorylation thereby contributes to EGFR-TKI resistance in the mutant (MT)-EGFR LUAD cells. Meanwhile, IL-17A enhances EGF-induced EGFR activation via attenuating EGFR degradation in wild type (WT)-EGFR LUAD cells.

Conclusions: Our results revealed the diverse impacts of IL-17A on EGFR activation in WT and MT EGFR LUAD cellsand suggested IL-17A as a potential therapeutic target in treating LUAD and overcoming EGFR-TKI resistance.