Nicotine-induced PD-L1 expression in lung squamous cell carcinoma is mediated by the α7-nAChR/STAT3 signaling pathway.

BACKGROUND

Nicotine, the principal addictive component of tobacco smoke, promotes lung cancer cell proliferation via α7 nicotinic acetylcholine receptors (α7-nAChRs). Programmed death-ligand 1 (PD-L1) serves as a crucial predictive biomarker for immune checkpoint inhibitor (ICI) therapy in lung squamous cell carcinoma (LUSC). This study aimed to investigate the expression patterns of α7-nAChR and its encoding gene in LUSC tissues, and to evaluate their associations with PD-L1 expression.

METHODS

expression, its correlation with clinicopathological features, and survival outcomes in LUSC were analyzed using The Cancer Genome Atlas (TCGA) database and Kaplan-Meier plotter. The expression levels of α7-nAChR and PD-L1 in LUSC tissues and cell lines were evaluated by immunohistochemistry and Western blot (WB). Following nicotine stimulation and small interfering RNA (siRNA) transfection, messenger RNA (mRNA) expression levels of , signal transducer and activator of transcription 3 (STAT3), and CD274 (PD-L1) were quantified using quantitative real-time polymerase chain reaction (qRT-PCR), while their protein levels were assessed by WB.

RESULTS

expression was significantly elevated in LUSC tissues and cell lines compared to adjacent normal tissues and bronchial epithelial cell lines (P<0.05), and correlated with smoking status. Higher expression was associated with shorter overall survival. Nicotine stimulation (1.0 μM) significantly increased the mRNA expression levels of , STAT3, and CD274 in LUSC cell lines. Knockdown of siRNA-mediated in LUSC cell lines decreased STAT3 phosphorylation (pSTAT3) and PD-L1 protein levels, while attenuating nicotine-induced PD-L1 upregulation. STAT3 silencing had no significant effect on α7-nAChR protein expression but downregulated PD-L1 protein levels and attenuated nicotine-induced PD-L1 upregulation.

CONCLUSIONS

α7-nAChR and its encoding gene are upregulated in LUSC tissue and are associated with smoking status. Patients with high expression of have a relatively worse prognosis. Nicotine may upregulate PD-L1 expression in LUSC through the α7-nAChR/STAT3 pathway.