Monocyte programmed death ligand-1 expression after 3–4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study

Abstract

BackgroundSeptic shock is a major healthcare problem with a high mortality rate that might be caused by immunosuppression. Programmed cell death receptor-1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1), which are co-inhibitory receptor molecules, participate in sepsis-induced immunosuppression. In this study, we investigated which PD-1-related molecules can be used to evaluate the risk stratification and prognosis of septic patients. Furthermore, we explored the prognostic significance of a combination of ideal predictors and conventional clinical risk parameters in septic shock patients.MethodsIn total, 29 healthy controls, 59 septic patients, and 76 septic shock patients were enrolled in this study. Considering that the focus of the research was on the second phase of sepsis, blood samples were obtained at days 3–4 after the onset of systemic inflammatory response syndrome (SIRS). PD-1 and PD-L1 expression were measured on circulating CD4+ T cells, CD8+ T cells, and monocytes (PD-L1 only) by flow cytometry.ResultsOur results showed that only monocyte PD-L1 expression gradually increased, based on the increasing severity of disease (P < 0.001). Similarly, multivariate logistic regression analysis showed that only monocyte PD-L1 expression was an independent predictor of 28-day mortality in septic shock patients. Area under the receiver operating characteristic curve analysis of the combination of monocyte PD-L1 expression and conventional clinical risk parameters indicated a more significant prognostic ability than analysis of each parameter alone.ConclusionOur study demonstrated that, among PD-1-related molecules, only monocyte PD-L1 expression after 3–4 days of sepsis was associated with risk stratification and mortality in septic patients. Furthermore, measurement of monocyte PD-L1 expression was a promising independent prognostic marker for septic shock patients.

Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression

“…This study showed some remarkable results because the inhibitory receptor expressions were comparatively low at the onset of sepsis but increased significantly over time as sepsis progressed [56, 73]. Another prospective clinical study also showed that severe sepsis caused a significant increase in PD-1 expression on CD4+ and CD8+ T lymphocytes and PD-L1 on monocytes, and furthermore monocyte PD-L1 expression on monocytes served as an independent predictor of 28-day mortality in septic shock patients [74, 75]. Shubin et al showed that BTLA expression was significantly increased on circulating CD4+ T cells and B cells in septic mice, which was associated with loss of these cells [76].…”

Towards precision medicine for sepsis patients

“…As such, it can be envisioned that profiling of cellular metabolism provides a snapshot of the current immunological state of a septic patient and may be used to guide treatment. Furthermore, the programmed death 1 (PD-1) pathway appears to be of particular relevance in sepsis-induced immune suppression, and expression of PD-L1 (the ligand for PD-1) on the cell surface of monocytes is associated with risk stratification and mortality in septic patients [11]. As ex vivo addition of antibodies against PD-1 or PD-L1 restored function of monocytes, neutrophils, T cells, and natural killer (NK) cells [12], the data from clinical studies in the field of oncology that show that treatment with anti-PD-1/PD-L1 antibodies is feasible and safe [13] is of interest to the sepsis field.…”

Emerging infection and sepsis biomarkers: will they change current therapies?

“…These receptors have been implicated in T-cell exhaustion: unrelenting antigen exposure causes loss of T-cell function [25]. Several studies have demonstrated that these molecules are up-regulated in sepsis, making it a candidate biomarker and a candidate therapeutic target [124–126]. In animal studies, inhibition of PD-1 or PD-L1, either through genetic modification or introduction of an antibody, resulted in improved survival and decreased lymphocyte apoptosis [127–130].…”

“…Although the sample sizes were small, two studies found that increased percentage of PD-1 class molecules were seen in non-survivors [124, 126]. Additionally, higher expression of PD-L1 and PD-L2 on monocytes at day 3–5 of illness was associated with the development of secondary nosocomial infections [125].…”

“…Additionally, higher expression of PD-L1 and PD-L2 on monocytes at day 3–5 of illness was associated with the development of secondary nosocomial infections [125]. The AUC of monocyte PD-L1 percentage to predict 28-day mortality was 0.73; and higher levels of this ligand were seen in patients with septic shock when compared to those who did not develop shock [124]. This early work suggests PD-1 class molecules could help with prognostics, and offers a novel treatment adjunct.…”