Two new immature and dysfunctional neutrophil cell subsets define a predictive signature of sepsis useable in clinical practice

Abstract

One Sentence Summary:CD123 + and/or PD-L1 + immature and dysfunctional neutrophil subsets identified by mass cytometry, define an early human blood signature of sepsis Abstract:Sepsis is the leading cause of death in adult intensive care units. At present, sepsis diagnosis relies on non-specific clinical features. It could transform clinical care to have objective immune cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Here, high dimensional mass cytometry was used to reveal for the first time a specific neutrophil signature of sepsis severity that does not overlap with other inflammatory biomarkers, and that distinguishes patients with sepsis from those with non-infectious inflammatory syndrome. Unsupervised analysis of 42-dimesional mass cytometry data characterized previously unappreciated heterogeneity within the CD64 + immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 expression. These immature neutrophils exhibited diminished activation and phagocytosis functions.The proportion of CD123-expressing neutrophils also correlated with clinical severity. Critically, this study showed that these two new neutrophil subsets were specific to sepsis and detectable by routine flow cytometry using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.

LOX-1+ immature neutrophils predict severe COVID-19 patients at risk of thrombotic complications

“…Numerous studies have shown an association between circulating immature neutrophils and bacterial sepsis (21). Here, we provided evidence that this immature subset may serve as a severity biomarker in We recently reported that the proportion of CD123-expressing immature neutrophils correlated with bacterial sepsis severity (17). Here, we showed that the expression of CD123 on CD10 -CD64 + neutrophils was related to a higher SOFA score among critically-ill COVID-19 patients.…”

“…Expert-gating strategy confirmed the high abundance of CD10 -CD64 + neutrophils among ICU patients compared non-ICU patients ( Figure 1B and Supplementary Figure S2 for cell counts). Then, we compared the expression of CD123, LOX-1 and PD-L1 surface molecules, formerly known as dysregulated in sepsis (17). All three of them were barely coexpressed on neutrophils and lead to the identification of three distinct neutrophil subpopulations ( Figure 1C and data not shown).…”

“…Principal Component Analyses were performed with R software 3.3.1. Whole blood immunostaining was performed, within 3h after blood drawing, using a previously published panel designed to give a precise evaluation of immature circulating neutrophils (17).…”

“…We previously identified two new CD10 -CD64 + neutrophil subsets expressing either PD-L1 or CD123 that were specific to bacterial sepsis (17). In addition to these markers, previous work showed that LOX-1 is an important mediator of inflammation and neutrophils dysfunction in sepsis and cancers (18,19).…”

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

“…Indeed, CD62L downregulation and high PD-L1 expression has been frequently associated with suppressive function of neutrophils and granulocytic myeloid-derived suppressor cells (gMDSCs) ( Bronte et al., 2016 ; Cassetta et al., 2019 ; Kamp et al., 2012 ; Pillay et al., 2012 ; Tak et al., 2017 ; Testa et al., 2004 ; Younos et al., 2015 ). Interestingly, a recent study described a high abundance of similar immature and dysfunctional CD64 + and PD-L1 + neutrophils in sepsis patients ( Meghraoui-Kheddar et al., 2020 ).…”