Abstract
BackgroundSepsis remains a major cause of mortality in critical care, for which specific treatments are lacking. The dysregulated response to infection seen in sepsis includes features of lymphocyte dysfunction and exhaustion, suggesting that immune-stimulatory therapy may improve outcomes in certain patient groups. Monoclonal antibodies targeting checkpoint molecules, such as programmed-death 1 protein (PD-1) and its ligand PD-L1, have shown success in stimulating the immune response in patients with cancer, and are being considered for future sepsis trials. The aims of this pilot study were to compare lymphocyte subset expression of PD-1 and its ligands between patients with sepsis and controls; to characterize serum levels of PD-1 and PD-L1 in patients with sepsis and controls, and determine if serum concentrations correlated with cell surface expression.MethodsExpression levels of PD-1, PD-L1 and PD-L2 on four lymphocyte subsets (CD27 + CD19+ B cells, CD27-CD19+ B cells, CD27 + CD4+ T cells and CD27-CD4+ T cells) were compared between 22 patients with sepsis (including 11 survivors and 11 non-survivors) and 11 healthy controls using flow cytometry. Levels of soluble PD-1 and PD-L1 were also compared using commercially available ELISA kits.ResultsExpression of PD-1 and PD-L1 was higher on all lymphocyte subsets in patients with sepsis compared to controls (p < 0.05). PD-L2 expression on CD27+ B cells was also higher in patients with sepsis (p = 0.0317). There was differential expression of PD-1 by CD27 status, with expression being higher in the B and T cell subsets associated with memory status (CD27+ and CD27-, respectively; p < 0.001). Higher PD-1 and PD-L1 expression was not associated with mortality or with a higher risk of nosocomial infection. There were no differences in levels of soluble PD-1 or PD-L1 between patients with sepsis and controls.ConclusionsHigher expression of PD-1 by memory subpopulations of B cells and CD4+ T cells, with normal soluble PD-1 and PD-L1 in patients with sepsis, are novel findings. This information may be useful to enrich sepsis populations for trials of PD-1/PD-L1 blockade.
Highlights
Sepsis remains a major cause of mortality in critical care, for which specific treatments are lacking
As this dysfunction is potentially reversible with anti-Programmed death protein 1 (PD-1) or anti-programmed death ligand-1 (PD-L1) monoclonal antibody treatment [2, 5,6,7,8], manipulating the PD-1 pathway represents a potential target for sepsis trials
Our conceptual approach was that sepsis trial eligibility criteria are often assessed on the day of intensive care unit (ICU) admission and that patients with increased expression of PD-1 and PD-L1 have a greater risk of nosocomial infections and/or death, as this would be a dominant mechanism contributing to these outcomes
Summary
Sepsis remains a major cause of mortality in critical care, for which specific treatments are lacking. Monoclonal antibodies targeting checkpoint molecules, such as programmed-death 1 protein (PD-1) and its ligand PD-L1, have shown success in stimulating the immune response in patients with cancer, and are being considered for future sepsis trials The aims of this pilot study were to compare lymphocyte subset expression of PD-1 and its ligands between patients with sepsis and controls; to characterize serum levels of PD-1 and PD-L1 in patients with sepsis and controls, and determine if serum concentrations correlated with cell surface expression. As this dysfunction is potentially reversible with anti-PD-1 or anti-PD-L1 monoclonal antibody treatment [2, 5,6,7,8], manipulating the PD-1 pathway represents a potential target for sepsis trials Against this background, we hypothesized that lymphocyte surface PD-1, PD-L1 and PD-L2 expression by B and T cell subsets will vary by CD27 expression status. We hypothesized that cell-surface PD-1, PD-L1 and PD-L2 expression would correlate with serum concentrations, and so we measured corresponding serum PD-1 and PD-L1 levels in the same samples
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