High levels of monocytic myeloid-derived suppressor cells are associated with favorable outcome in patients with pneumonia and sepsis with multi-organ failure

Abstract

Background Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunosuppressive functions sub-classified into monocytic and polymorphonuclear MDSCs (M-MDSCs and PMN-MDSCs). Clinical studies reported increased levels of MDSCs that were associated with poor outcome in sepsis patients. Since sepsis patients exhibit signs of inflammation and immunosuppression, MDSCs may provide benefit by dampening deleterious inflammation in some patients. To test this hypothesis, we measured MDSCs in critically ill sepsis patients with pneumonia and multi-organ dysfunctions and a high likelihood of death. Methods This was a prospective multicenter observational cohort study performed in eight ICUs in Athens and Thessaloniki, Greece, enrolling critically ill patients with pneumonia and sepsis with multi-organ dysfunctions. A flow cytometry approach using blood collected at study inclusion in tubes containing lyophilized antibodies combined to unsupervised clustering was developed to quantify M-MDSCs and PMN-MDSCs. Results Forty-eight patients were included, of whom 34 died within 90 days. At study inclusion, M-MDSCs and PMN-MDSCs were increased in sepsis patients when compared to healthy subjects (3.07% vs 0.96% and 22% vs 2.1% of leukocytes, respectively; p < 10–4). Increased PMN-MDSCs were associated with secondary infections (p = 0.024) and new sepsis episodes (p = 0.036). M-MDSCs were more abundant in survivors than in patients who died within 28 days (p = 0.028). Stratification of patients according to M-MDSC levels revealed that high levels of M-MDSC were associated with reduced 90-day mortality (high vs low M-MDSCs: 47% vs 84% mortality, p = 0.003, hazard ratio [HR] = 3.2, 95% CI 1.4–7.2). Combining high M-MDSC levels with low Acute Physiology and Chronic Health Evaluation (APACHE) II score improved patient stratification (M-MDSCshigh/APACHE IIlow vs M-MDSCslow/APACHE IIlow: 20% vs 80% 90-day mortality, p = 0.0096, HR = 7.2, 95% CI 1.6–32). In multivariate analyses high M-MDSCs remained correlated with improved survival in patients with low APACHE II score (p = 0.05, HR = 5.26, 95% CI 1.0–27.8). Conclusion This is the first study to associate high levels of M-MDSCs with improved survival in sepsis patients.

Integrated machine learning approaches for flow cytometric quantification of myeloid-derived suppressor cells in acute sepsis

“…This observation is especially significant since ( 1 ) we analyzed whole blood (rather than PBMC), and ( 2 ) it is therefore likely that a portion of these scant PMN-MDSCs are mature neutrophils, since CD11b + CD15 + CD14 − CD33 +/low CD66b + markers enrich for neutrophils at all maturation stages ( 10 ). High PMN-MDSCs within the first week of sepsis onset have been recently associated with secondary infections, while M-MDSCs appear to be more abundant in sepsis survivors ( 26 ). While MDSCs are known to expand and acquire their suppressive potential during protracted sepsis ( 13 ), there is limited human data about the kinetics and immune function of this population in early sepsis.…”

Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis

“…Furthermore, in a model of asthma, PMN-MDSCs can inhibit the function of Th2 cells and suppress inflammation ( 58 ) in a PGE2 and COX-1 dependent manner. However, in COVID-19 early expansion of MDSCs is predictive of a poor outcome by preventing viral clearance, yet in late disease, they can be beneficial by reducing secondary inflammation ( 59 ). As will be discussed later MDSCs can be beneficial in preventing inflammation in chronic viral hepatitis ( 60 ).…”

Immunomodulatory actions of myeloid-derived suppressor cells in the context of innate immunity

“… 74 , 89 Furthermore, this opinion for the dual role of MDSCs in sepsis could be strengthened by the recent study of Schrijver et al, who enrolled critically ill patients with pneumonia and sepsis with multi-organ failure and correlated for the first time the increased counts of M-MDSCs with better survival of the patients. 90 …”