Elevated Plasma Soluble PD-L1 Levels in Out-of-Hospital Cardiac Arrest Patients

Abstract

Background: A deregulated immune system has been implicated in the pathogenesis of post-cardiac arrest syndrome (PCAS). A soluble form of programmed cell death-1 (PD-1) ligand (sPD-L1) has been found at increased levels in cancer and sustained inflammation, thereby deregulating immune functions. Here, we aim to study the possible involvement of sPD-L1 in PCAS. Methods: Thirty out-of-hospital cardiac arrest (OHCA) patients consecutively admitted to the ER of Mie University Hospital were prospectively enrolled. Plasma concentrations of sPD-L1 were measured by an enzyme-linked immunosorbent assay in blood samples of all 30 OHCA patients obtained during cardiopulmonary resuscitation (CPR). In 13 patients who achieved return-of-spontaneous-circulation (ROSC), sPD-L1 levels were also measured daily in the ICU. Results: The plasma concentrations of sPD-L1 in OHCA were significantly increased; in fact, to levels as high as those observed in sepsis. sPD-L1 levels during CPR correlated with reduced peripheral lymphocyte counts and increased C-reactive protein levels. Of 13 ROSC patients, 7 cases survived in the ICU for more than 4 days. A longitudinal analysis of sPD-L1 levels in the 7 ROSC cases revealed that sPD-L1 levels occurred in parallel with organ failure. Conclusions: This study suggests that ischemia- reperfusion during CPR may aberrantly activate immune and endothelial cells to release sPD-L1 into circulation, which may play a role in the pathogenesis of immune exhaustion and organ failures associated with PCAS.

Intra‐arrest blood‐based biomarkers for out‐of‐hospital cardiac arrest: A scoping review

“…The search strategy identified a total of 11,834 records, of which 6914 were non‐duplicates. After applying all inclusion and exclusion criteria, 118 studies were included in the scoping review, as shown in Figure 1 11–128 …”

Divergent roles of PD-L1 in immune regulation during ischemia–reperfusion injury

“…Although few studies on PD-L1 in the context of I/R exist, their results are contradictory. For instance, they report that during I/R, PD-L1: 1) is either upregulated or downregulated, 2) promotes or limits inflammation, 3) increases or decreases leukocyte recruitment, and 4) implicates either BMDCs or non-BMDCs (29,30,(61)(62)(63)(64)(65)(66)(67)(68)(69). Of course, we could attribute these differences to differences between experimental conditions, materials, methods, or animal models.…”

“…Changes in PD-L1 expression have been shown to be correlated with I/R injury in multiple models. A clinical study on 30 out-of-hospital cardiac arrest (OHCA) patients indicates that their sPD-L1 plasma levels increased during cardiopulmonary resuscitation (CPR) and were significantly higher than those of healthy volunteers (61). Considering that previous studies have indicated that sPD-L1 is elevated not only in cancer but also in general inflammation (43, 70, 71), other inflammatory disturbances were considered in this study.…”

“…The study of the central nervous system (CNS) is further complicated by the existence of the blood–brain barrier (BBB) ( 75 ). Halina Offner and her team conducted a series of studies on the role of the PD-1/PD-L1 costimulatory pathway in experimental stroke ( 67 , 68 , 76 ).…”