The TLR4/ERK/PD‑L1 axis may contribute to NSCLC initiation.

Abstract

Infection and inflammation serve an important role in tumor development. Toll-like receptor 4 (TLR4) is a pivotal component of the innate and adaptive immune response during infection and inflammation. Programmed-death ligand 1 (PD-L1) is hypothesized as an important factor for non-small cell lung cancer (NSCLC) immune escape. In the present study, the relationship between TLR4 and PD-L1, in addition to the associated molecular mechanism, were investigated. TLR4 and PD-L1 expression in lung cancer tissues were detected using immunohistochemistry, whilst overall patient survival was measured using the Kaplan-Meier method. The A549 cell line stimulated using lipopolysaccharide (LPS) was applied as the in vitro inflammatory NSCLC model. Associated factors were investigated using reverse transcription-quantitative PCR and western blotting. Lung cancer tissues exhibited increased PD-L1 and TLR4 levels compared with those of adjacent para-cancerous tissues, where there was a positive correlation between TLR4 and PD-L1 expression. In addition, increased expression of these two proteins was found to be linked with poorer prognoses. Following the stimulation of A549 cells with LPS, TLR4 and PD-L1 expression levels were revealed to be upregulated in a dose-dependent manner, where the ERK and PI3K/AKT signaling pathways were found to be activated. Interestingly, in the presence of inhibitors of these two pathways aforementioned, upregulation of PD-L1 expression was only inhibited by the MEK inhibitor PD98059, which can inhibit ERK activity. These data suggested that the ERK signaling pathway is necessary for the TLR4/PD-L1 axis. In conclusion, data from the present study suggest that TLR4 and PD-L1 expression can serve as important prognostic factors for NSCLC, where TLR4 activation may induce PD-L1 expression through the ERK signaling pathway.