Background: The tumor microenvironment plays a key role in non-small cell lung cancer (NSCLC) development and also influences the effective response to immunotherapy. The pro-inflammatory factor interleukin-17A mediates important immune responses in the tumor microenvironment. In this study, the potential role and mechanisms of IL-17A in NSCLC were investigated.
Methods: We detected IL-17A by immunohistochemistry (IHC) in 39 NSCLC patients. Its expression was correlated with the programmed cell death-ligand1 (PD-L1). IL-17A knockdown and overexpression in A549 and SPC-A-1 cell models were constructed. The function of IL-17A was examined in vitro by wound healing, migration, invasion, plate colony formation and T cell killing assay. Western blot analysis, immunofluorescence assay and IHC were performed to investigate the regulation effects of IL-17A on autophagy in A549 and SPC-A-1. The effect of IL-17A on ROS/Nrf2/p62 signaling pathway was detected. Subcutaneous tumor models were established to examine the tumor-promoting effect of IL-17A in vivo and its effect on immunotherapy.
Results: We found a prevalent expression of IL-17A in NSCLC tumor tissues and it was positively correlated with PD-L1 expression (r = 0.6121, p < 0.0001). In vitro, IL-17A promotes lung cancer cell migration, invasion and colony formation ability. Moreover, IL-17A upregulated N-cadherin, Twist, and Snail, and downregulated E-cadherin in NSCLC cells. IL-17A enhanced cell survival in the T cell killing assay. Mechanistically, IL-17A induced ROS production and increased Nrf2 and p62 expression, thereby inhibiting autophagy and reducing PD-L1 degradation. In vivo experiments, anti-IL-17A monoclonal antibody alone slowed the growth of subcutaneous tumors in mice. When combined with anti-PD-L1 monoclonal antibody, tumor tissue expression of PD-L1 was reduced and the therapeutic effect was diminished.
Conclusion: We found that IL-17A promoted NSCLC progression and inhibited autophagy through the ROS/Nrf2/p62 pathway leading to increased PD-L1 expression in cancer cells. Modulation of IL-17A may affect the therapeutic efficacy of immunotherapy.
Keywords: Autophagy; Immunotherapy; Interleukin-17A; NSCLC; PD-L1.
© 2023. The Author(s).