Extracellular vesicles derived from lung cancer cells exposed to intermittent hypoxia upregulate programmed death ligand 1 expression in macrophages

作者：Yuanling Liu, Minzhen Lu, Jianan Chen, Siqi Li, Yiyu Deng, Shifang Yang, Qiong Ou, Jing Li, Ping Gao, Zeru Luo, Ping Yuan, Jianlong Tan, Xinglin Gao · 发表于：Sleep And Breathing · 年份：2021 · DOI：10.1007/s11325-021-02369-1 · 被引用次数：23 · 研究领域：Extracellular vesicles in disease、Nanoplatforms for cancer theranostics、Cancer, Hypoxia, and Metabolism

Abstract Purpose Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), compromises immune surveillance through the upregulation of programmed cell death-1 ligand (PD-L1). Tumor-released extracellular vesicles (EVs) have been reported to modulate immunosuppressive activities. We investigated whether or not EVs derived from intermittent hypoxic lung cancer cells can alter the expression of PD-L1 in macrophages. Methods The expression of PD-L1 + monocytes from 40 patients with newly diagnosed non-small-cell lung cancer (NSCLC) and with ( n =21) or without ( n =19) OSA were detected. Plasma EVs isolated from NSCLC patients with moderate–severe OSA ( n =4) and without OSA ( n =4) were co-cultured with macrophages. A549 cells were exposed to normoxia or IH (48 cycles of 5 min of 1% O 2 hypoxia, followed by 5 min of normoxia). EVs were isolated from cell supernatant and were co-cultured with macrophages differentiated from THP-1. PD-L1 and hypoxia-inducible factor-1 α (HIF-1α) expressions were measured by flow cytometry, immunofluorescence, and Western blot analysis. Results PD-L1 + monocytes were elevated in NSCLC patients with OSA and increased with the severity of OSA and nocturnal desaturation. PD-L1 + macrophages were induced by EVs from NSCLC patients with OSA and positively correlated with HIF-1α expressions. EVs from IH-treated A549 can promote PD-L1 and HIF-1α expression in macrophages and the upregulation of PD-L1 expression was reversed by specific HIF-1...