Soluble PD-L1 is a potential biomarker of cutaneous melanoma aggressiveness and metastasis in obstructive sleep apnoea patients

Abstract

Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity of OSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects.

Targeting intermittent hypoxia downstream pathways for biomarker discovery and new treatment perspectives in cutaneous melanoma

“…In view of these results, the study by CUBILLOS-ZAPATA et al [16] does indeed allow proposal of sPD-L1 as a potential biomarker of cutaneous melanoma aggressiveness and metastasis in OSA patients. This is also reinforced by the fact that PD-L1 expression is upregulated by intermittent hypoxia, a major hallmark of OSA, as previously demonstrated by the same group [20] and by others [22,30].…”

“…Finally, the study of CUBILLOS-ZAPATA et al [16] is certainly important and by far the largest prospective multicentre study in the field, and the authors should be congratulated for this. However, as acknowledged by the authors themselves, sleep fragmentation, a major confounding mechanistic factor, has not been assessed in the current study.…”

“…In the current issue of the European Respiratory Journal, CUBILLOS-ZAPATA et al [16] propose soluble programmed cell death ligand 1 (sPD-L1) as a potential biomarker of cutaneous melanoma aggressiveness and metastasis in OSA patients. This is quite relevant in view of the major role of the programmed cell death receptor 1 (PD-1)/PD-L1 axis in melanoma development [15,17], aggressiveness [18] and survival [19], but also because of its upregulation by intermittent hypoxia and by the hypoxia-inducible factor (HIF)-1 transcription factor in cutaneous melanoma cells (figure 1) [20][21][22].…”

“…In their multicentre cross-sectional observational study including 360 patients with newly diagnosed cutaneous melanoma, CUBILLOS-ZAPATA et al [16] compared plasma sPD-L1 levels according to the presence and severity of OSA, and evaluated relationships with cutaneous melanoma aggressiveness and invasiveness [16]. Patients were divided into four groups (non-OSA, mild OSA, moderate OSA and severe OSA) according to their apnoea-hypopnoea index (AHI) assessed by overnight respiratory polygraphy.…”

Sleep apnoea and immune regulation: The story is only beginning

“…However, concomitant upregulation of PD‐L1 and HIF‐1α could be also explained by co‐expression, and much remains to be explored regarding the mechanisms of upregulation of PD‐L1 or the PD‐L1/PD‐1 axis in OSA. The overexpression of PD‐L1 on peripheral blood monocytes as a non‐invasive biomarker of immune challenge from sleep‐disordered breathing is another exciting possibility to be studied, while soluble PD‐L1 as a potential biomarker for melanoma aggressiveness and metastasis in OSA has just been reported by the authors …”