Nicotinic acetylcholine receptor subunit alpha 7 mediates cigarettes smoke-induced PD-L1 expression in human bronchial epithelial cells

Abstract

Introduction: Tobacco smoking is the top risk factors for lung cancer. Nicotine in cigarette smoke can induce addiction, and its derivatives could be potent carcinogens after metabolic activation. Lung cancer from smokers usually showed higher PD-L1 expression levels and appeared to be more responsive than non-smokers to immune-checkpoint inhibitors. This study aimed to investigate whether activation of nicotinic acetylcholine receptor subunit α7 (nAChRα7) expression would induce PD-L1 expression. Methods: Expression levels of nAChRα7 and PD-L1 in eight human bronchial epithelial cell lines (HBECs) were measured after treatment with cigarette smoke extract (CSE) or nicotine derivative. Results: nAChRα7 was highly expressed in lung squamous cell carcinoma tissue as well as in normal lung tissue from smokers. PD-L1 expression levels increased in HBECs after exposure to CSE and nicotine derivative. This induction of PD-L1 expression by CSE could be diminished by nAchRα7 small-interfering RNA, with relevant signalling mediated via STAT3 phosphorylation or NRF2 expression. This study demonstrated the linkage on the well-known nicotine derivative-activated nAChRα7-induced STAT3/NRF2 pathways and revealed PD-L1 as the downstream signalling target in normal lung epithelial cells. Conclusion: This may provide insight into the possible mechanism of cigarette smoke-induced pre-cancerous immune invasion mediated through nicotine and its derivative, with activation of nAChRα7-induced STAT3/NRF2 pathways leading to cellular growth and proliferation.