Abstract

PurposeIntermittent 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.MethodsThe 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% O2 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.ResultsPD-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-1α inhibitor.ConclusionIH can enhance the function of EVs derived from lung cancer cells to aggravate immunosuppressive status in macrophages. HIF-1α may play an important role in this process.

Highlights

  • Obstructive sleep apnea (OSA) is a relatively common disease characterized by recurrent total or partial upper airway collapse during sleep

  • We found that programmed cell death-1 ligand (PD-L1)+monocytes were overexpressed in non-small-cell lung cancer (NSCLC) patients with obstructive sleep apnea (OSA) and increased with the severity of OSA and nocturnal desaturation

  • We found that the expressions of PD-L1 on monocytes were elevated in NSCLC patients with OSA and were positively correlated with the apnea-hypopnea index (AHI) and Oxygen desaturation index (ODI)

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Summary

Introduction

Obstructive sleep apnea (OSA) is a relatively common disease characterized by recurrent total or partial upper airway collapse during sleep. This is related with intermittent hypoxia (IH) and sleep fragmentation. Some large cohort studies have found evidences that OSA promotes cancer development and increases cancer mortality [1,2,3,4]. Some in vivo and in vitro studies show that intermittent hypoxia influences cancer cell behavior and promotes lung cancer metastasis [5,6,7]. Marta Torres et al found that IH promoted lung cancer aggressiveness through alterations in the host immune response in a murine model of OSA [8]

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