Septic shock triggers a complex immune response characterized by the coexistence of hyperinflammation and immunosuppression, the latter being a major driver of ICU-acquired infections and increased mortality. Currently, the most established biomarkers for assessing sepsis-induced immunosuppression rely on flow cytometry—a technique not universally available in clinical practice. In contrast, soluble biomarkers are, in principle, easier to measure. Although assays for soluble PD-L1 (sPD-L1) are not yet standardized, sPD-L1 concentrations may represent a pragmatic alternative, given the putative role of PD-1/PD-L1 signaling in immunosuppressive pathways during sepsis. In this study, we investigated sPD-L1 in relation to established cellular markers of immunosuppression in a cohort of 161 patients with septic shock. sPD-L1 levels were measured using the ELLA microfluidic platform during the first week of ICU admission. We assessed their association with clinical outcomes and explored the relationship between sPD-L1 and immunosuppressive profiles defined by low monocytic HLA-DR expression (mHLA-DR) and absolute lymphocyte count.

Upon admission, patients exhibited elevated sPD-L1 levels compared to healthy controls (medians: 179 vs. 54 pg/mL, p < 0.001). No correlation was observed between sPD-L1 levels and severity scores (SOFA, SAPS II). Elevated sPD-L1 was independently and significantly associated with increased mortality at both 28 and 90 days. Longitudinal analysis using K-means clustering revealed that the cluster with consistently highest sPD-L1 levels was associated with unfavorable outcomes. Overall, and at any single time point, sPD-L1 concentrations did not correlate with mHLA-DR expression or lymphopenia. However, the combined presence of high sPD-L1 and low mHLA-DR levels at the end of the first week identified a subgroup of patients with particularly poor clinical outcomes.

These findings highlight the potential of sPD-L1 as a clinically relevant biomarker in the context of sepsis immunopathology. Further studies are warranted to elucidate its role in the mechanisms underlying sepsis-induced immunosuppression. Such insights could support the integration of sPD-L1 into multimodal biomarker panels for immune monitoring and risk stratification in patients with septic shock.