Programmed death-ligand 1 links with inflammatory and endothelial activation in pneumonia

Background Soluble programmed death-ligand 1 (sPD-L1) is often considered a marker of immunosuppression, proposed to reflect PD-1/PD-L1 signalling on immune cells. We aimed to investigate this premise and characterised plasma sPD-L1-associated immune responses in community-acquired pneumonia (CAP). Methods Plasma sPD-L1 and 60 biomarkers reflecting inflammation, vascular response, coagulation and cytokine/chemokine release were measured in CAP patients within 24 h after admission to a general hospital ward. Associations were analysed using both univariate and multivariable models. In patient subgroups, immune cell PD-1/PD-L1 was assessed by spectral flow cytometry and blood transcriptomes by RNA sequencing. Results CAP patients (n=226) were stratified into tertiles based on sPD-L1 levels. Admission disease severity scores were similar across groups. In-hospital mortality only occurred in the highest sPD-L1 tertile and in a continuous analysis sPD-L1 independently predicted 28-day mortality (overall 4.4%). Higher sPD-L1 was linked to plasma biomarker changes indicating increased systemic inflammation, cytokine release, and endothelial activation. sPD-L1 did not correlate with PD-L1 expression on monocytes or dendritic cells, nor with PD-L1 gene expression in whole blood. sPD-L1 did not associate with immunosuppression markers (IL-10, monocyte HLA-DR, and PD-1 on T cells). In patients with high sPD-L1, blood transcriptomes showed enrichment of haemostasis, endothelial activation, and systemic inflammation, but not of programmed cell death pathways. Conclusions In patients hospitalised with CAP plasma sPD-L1 does not reflect immune cell PD-L1 expression or immunosuppression, but rather systemic inflammation and endothelial activation.