Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

Cubillos‐Zapata, Carolina; Avendaño-Ortíz, José; Hernández-Jiménez, Enrique; Toledano, Víctor; Casas-Martín, José; Varela-Serrano, Aníbal; Torres, Marta; Almendros, Isaac; Casitas, Raquel; Fernández-Navarro, Isabel; García‐Sánchez, Aldara; Aguirre, Luis A.; Farré, Ramón; López-Collazo, Eduardo; García‐Río, Francisco

doi:10.1183/13993003.00833-2017

Cited by 91 publications

(87 citation statements)

References 37 publications

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“…However, our results suggest that the contribution of OSA‐dependent inflammation in elderly subjects is not sufficient to increase PD‐L1 expression compared to healthy subjects of the same age. In our opinion, this reinforces the fact that HIF‐1α activation induced by IH is the main factor contributing to the upregulation of PD‐L1 in patients with OSA, as previously described …”

Section: Discussionsupporting

confidence: 90%

“…Peripheral blood mononuclear cells (PBMC) were isolated from patients with severe OSA and from healthy volunteers (HV) by Ficoll‐Plus gradient from GEHealthcare Bio‐Sciences (Bukinghamshire, UK). The CD14 + cells were obtained using a monocyte isolation kit from Miltenyi Biotec (Bergisch Gladbach, Germany), as we previously described …”

Section: Methodsmentioning

confidence: 99%

“…The PD‐L1/PD‐1 immune checkpoint inhibits proliferation and effector functions of T‐cells, and it has been described that tumour cells and pathogens can use this natural control pathway to escape T‐cell response . In patients with OSA, we have reported that the PD‐L1/PD‐1 co‐inhibitory pathway is upregulated in a hypoxia‐dependent manner, inducing a decrease in T‐cell proliferative capacity and cytotoxicity …”

Section: Introductionmentioning

confidence: 90%

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

Cubillos‐Zapata

Balbás-García²,

Avendaño-Ortíz³

et al. 2019

Respirology

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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. RESULTS Study subjectsForty-one patients with severe OSA were prospectively recruited, including 21 young patients (age < 55 years)Respirology (2019) 24, 684-692Age-dependent PD-L1 upregulation in OSA † † P < 0.01 versus HV younger than 55 years. ‡ ‡ P < 0.01 versus HV older than 55 years. § § P < 0.05 versus patients with OSA older than 55 years. AHI, apnoea-hypopnoea index; FEV 1 , forced expiratory volume at 1 s; FVC, forced vital capacity; HDL, high-density lipoprotein; HV, healthy volunteer; LDL, low-density lipoprotein; OSA, obstructive sleep apnoea; SpO 2 , oxyhaemoglobin saturation.

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Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

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

Cubillos‐Zapata

Balbás-García²,

Avendaño-Ortíz³

et al. 2019

Respirology

Self Cite

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“…HIF similarly regulates programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling that functions principally in MDSC and CD8 + effector T cell direct interactions in patients with obstructive sleep apnea, a common cause of secondary pulmonary hypertension [115]. Such immune checkpoint inhibitors, including PD-L1, are often hypoxia-response element genes themselves.…”

Section: Myeloid-derived Suppressor Cells and Pulmonary Hypertensionmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells and Pulmonary Hypertension

Bryant

Mehrad

Brusko

et al. 2018

IJMS

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Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.

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“…report the interesting finding that upregulation of programmed death‐ligand 1 (PD‐L1) expression correlating with hypoxia‐inducible factor (HIF)‐1 expression in monocytes of patients with OSA was only seen in the younger (<55 years) but not in older patients (>55 years), with comparable severity of OSA and intermittent hypoxia (IH), corroborated by findings in an IH model of young versus older mice. This work is pursuant upon their previous report of hypoxia‐dependent PD‐L1/programmed cell death‐1 (PD‐1) upregulation resulting in impairment of T‐cell proliferative capacity and cytotoxicity in sleep apnoea …”

mentioning

confidence: 99%