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

作者：Liu, Yuanling; Lu, Minzhen; Chen, Jianan; Li, Siqi; Deng, Yiyu; Yang, Shifang; Ou, Qiong; Li, Jing; Gao, Ping; Luo, Zeru; Yuan, Ping; Tan, Jianlong; Gao, Xinglin^*

来源：Sleep and Breathing, 2022, 26(2): 893-906.

DOI：10.1007/s11325-021-02369-1

• Obstructive sleep apnea
• Non-small-cell lung cancer
• Extracellular vesicle
• Programmed cell death-1 ligand
• Macrophage

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 alpha (HIF-1 alpha) 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-1 alpha expressions. EVs from IH-treated A549 can promote PD-L1 and HIF-1 alpha expression in macrophages and the upregulation of PD-L1 expression was reversed by specific HIF-1 alpha inhibitor. Conclusion IH can enhance the function of EVs derived from lung cancer cells to aggravate immunosuppressive status in macrophages. HIF-1 alpha may play an important role in this process.

• 单位
  南方医科大学; 广东省人民医院