Nicotinic Acetylcholine Receptor Subunit α7 Mediates Cigarette Smoke-Induced PD-L1 Expression in Human Bronchial Epithelial Cells.

Abstract

Simple SummaryLung cancer is strongly associated with tobacco smoking. Nicotine in tobacco smoke can be transformed into a carcinogen after in vivo metabolism. However, the mechanism of how nicotine metabolites modulate a pro-tumorigenic microenvironment remains largely unknown. We have explored the effects of nicotine stimulation on nicotinic acetylcholine receptor subunit alpha 7 (nAChRα7)-mediated PD-L1 expression in human bronchial epithelial cells (HBECs). PD-L1 is an important protein contributing to cancer immune escape and is currently the key biomarker for lung cancer immunotherapy. Here, we found that the nicotine metabolite NNK can induce PD-L1 expression in HBECs by acting through the nicotine receptor nAChRα7. This study has a direct impact on the understanding of smoking-related changes in bronchial epithelial cells and potential immune escape in smoking-related carcinogenesis and has immuno-therapeutic implications via PD-L1 in lung cancer. Further studies are warranted to examine the upstream inhibition of PD-L1-related pathways, which could be mediated through nicotinic acetylcholine receptors in smokers, and may ultimately aid in the prevention and treatment of lung cancer.Tobacco smoking is the top risk factor for lung cancer development. Nicotine in cigarettes can induce addiction, and its derivatives become potent carcinogens after metabolic activation and activate oncogenic signaling in lung epithelial cells through their expressed nicotinic acetylcholine receptors (nAChRs). However, the effects of smoking on the tumor immune microenvironment are under investigation. In the current study, we investigated whether nicotine activation of nicotinic acetylcholine receptor subunit α7 (nAChRα7, CHRNA7) would induce PD-L1 expression in lung epithelial cells. The expression levels of nAChRα7 and PD-L1 in eight human bronchial epithelial cell (HBEC) lines were measured after treatment with cigarette smoke extract (CSE) or nicotine derivatives. The results showed that PD-L1 expression levels increased in HBECs after exposure to CSE or nicotine derivatives. This induction of PD-L1 expression could be diminished by treatment with CHRNA7 small-interfering RNA, and the relevant signaling was mediated via STAT3 phosphorylation and NRF2 expression. In summary, this study demonstrated that the well-known nicotine derivative-activated nAChRα7 could induce STAT3/NRF2 pathways and subsequently promote PD-L1 expression in normal lung epithelial cells. This information provides mechanistic insight into cigarette smoke-induced immune evasion in lung epithelial cells.