Abstract
Sepsis is a pathology in which patients suffer from a proinflammatory response and a dysregulated immune response, including T cell exhaustion. A number of therapeutic strategies to treat human sepsis, which are different from antimicrobial and fluid resuscitation treatments, have failed in clinical trials, and solid biomarkers for sepsis are still lacking. Herein, we classified 85 patients with sepsis into two groups according to their blood oxygen saturation (SaO2): group I (SaO2 ≤ 92%, n = 42) and group II (SaO2 > 92%, n = 43). Blood samples were taken before any treatment, and the immune response after ex vivo LPS challenge was analyzed, as well as basal expression of PD-L1 on monocytes and levels of sPD-L1 in sera. The patients were followed up for 1 month. Taking into account reinfection and exitus frequency, a significantly poorer evolution was observed in patients from group I. The analysis of HLA-DR expression on monocytes, T cell proliferation and cytokine profile after ex vivo LPS stimulation confirmed an impaired immune response in group I. In addition, these patients showed both, high levels of PD-L1 on monocytes and sPD-L1 in serum, resulting in a down-regulation of the adaptive response. A blocking assay using an anti-PD-1 antibody reverted the impaired response. Our data indicated that SaO2 levels on admission have emerged as a potential signature for immune status, including PD-L1 expression. An anti-PD-1 therapy could restore the T cell response in hypoxemic sepsis patients with SaO2 ≤ 92% and high PD-L1 levels.
Highlights
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection [1]; it is currently a leading cause of death in intensive care units worldwide [2]
They participate in both phases of sepsis by firstly releasing inflammatory cytokines that contribute to a cytokine storm, and secondly adopting an immune depressive phenotype, whereupon they are unable to respond to secondary infections [4]
Since during hypoxemia the inhibition of prolyl hydroxylases (PHD) takes place, we examined the role of these enzymes in an in vitro model based on dimethyloxallyl glycine (DMOG)treatment before LPS stimulation (Figure 6A)
Summary
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection [1]; it is currently a leading cause of death in intensive care units worldwide [2]. Two phases have been recognized in this disease: an early inflammatory phase and a late immunosuppressive stage [4,5,6]; these two phases can overlap [4, 7] In this regard, monocytes/macrophages are believed to play an important role in orchestrating the host immune response during sepsis [4, 7]. Polarization of the adaptive response has been reported in lipopolysaccharide (LPS)-injected healthy donors and in murine polymicrobial sepsis [8] These observations highlight the importance of the interaction between monocytes and lymphocytes and its role in T cell exhaustion [6]. We and others have already reported programmed deathligand 1 (PD-L1) overexpression on sepsis monocytes [10,11,12,13], which was associated with risk stratification and mortality in these patients [14]
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