The TLR4/ERK/PD‑L1 Axis May Contribute to NSCLC Initiation

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.