Age‐dependent hypoxia‐induced PD‐L1 upregulation in patients with obstructive sleep apnoea

• Published in: Respirology (Carlton, Vic.) Vol. 24; no. 7; pp. 684 - 692
• Main Authors: Cubillos‐Zapata, Carolina, Balbás‐García, Cristina, Avendaño‐Ortiz, Jose, Toledano, Victor, Torres, Marta, Almendros, Isaac, Casitas, Raquel, Zamarrón, Ester, García‐Sánchez, Aldara, Feliu, Jaime, Aguirre, Luis A., Farre, Ramón, López‐Collazo, Eduardo, García‐Rio, Francisco
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.07.2019; Wiley Subscription Services, Inc
• Subjects: Adult; Age; Age Factors; Aged; Animal models; Animals; Apnea; Apoptosis; B7-H1 Antigen - blood; B7-H1 Antigen - genetics; Case-Control Studies; Cell death; elderly; Enzyme-linked immunosorbent assay; Female; Flow cytometry; Gene expression; Humans; Hypoxia; Hypoxia - blood; Hypoxia - etiology; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - blood; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; immune system; Immunosurveillance; intermittent hypoxia; L1 protein; Male; Mice; Middle Aged; Monocytes; Monocytes - metabolism; mRNA; PD-1 protein; PD-L1 protein; programmed cell death ligand‐1; Proteins; Respiratory diseases; RNA, Messenger; Sleep; Sleep Apnea, Obstructive - blood; Sleep Apnea, Obstructive - complications; Sleep Apnea, Obstructive - physiopathology; sleep apnoea; Sleep disorders; Splenocytes; Transcriptional Activation; Up-Regulation; immune system; sleep apnoea; intermittent hypoxia; programmed cell death ligand-1; elderly
• ISSN: 1323-7799; 1440-1843
• DOI: 10.1111/resp.13470

ABSTRACT Background and objective In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death‐1 (PD‐1) receptor and its ligand (PD‐L1). Because the risk of OSA‐related cancer depends on age, we assessed PD‐L1/PD‐1 expression in middle‐aged and older patients with OSA as well as in a murine model. Methods PD‐L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD‐L1 expression on monocytes and plasma PD‐L1 protein levels. Moreover, we analysed PD‐L1 expression on an in vivo IH model with old and young mice. Results In subjects up to 55 years of age, severe OSA increased PD‐L1 surface protein and mRNA level expression on monocytes and soluble‐PD‐L1 protein concentration in plasma compared to HV. PD‐L1 and hypoxia‐induced factor (HIF)‐1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD‐L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF‐1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD‐L1 expression in monocytes was related to HIF‐1α expression in young patients with OSA. Conclusion PD‐L1 upregulation in patients with OSA as a consequence of HIF‐1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity. Hypoxia‐induced upregulation of the programmed cell death‐1 receptor and its ligand (PD‐L1) may explain associations between sleep apnoea and cancer. This link may be age‐dependent but, contrary to expectations, this study shows that PD‐L1 upregulation in sleep apnoea occurs mainly in younger patients. See related Editorial