PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in Acute Respiratory...

The relationship between the PD-L1 (Programmed Death-Ligand 1)/PD-1 pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 [n = 59] and ARDS2 [n = 78]) or plasma samples alone (ARDS3 [n = 149]) collected from subjects with ARDS and tested for associations with mortality using multiple regression. We used mass cytometry to measure PD-L1/PD-1 expression and intracellular cytokine staining in cells isolated from BAL fluid (n = 18) and blood (n = 16) from critically ill subjects with or without ARDS enrolled from a fourth cohort. Higher plasma concentrations of sPD-L1 were associated with mortality in ARDS1, ARDS2, and ARDS3. In contrast, higher concentrations of sPD-L1 in the lung were either not associated with mortality (ARDS2) or were associated with survival (ARDS1). Alveolar PD-1^POS T cells had more intracellular cytokine staining than PD-1^NEG T cells. Subjects without ARDS had a higher ratio of PD-L1^POS alveolar macrophages to PD-1^POS T cells than subjects with ARDS. We conclude that sPD-L1 may have divergent cellular sources and/or functions in the alveolar versus blood compartments, given distinct associations with mortality. Alveolar leukocyte subsets defined by PD-L1 or PD-1 cell-surface expression have distinct cytokine secretion profiles, and the relative proportions of these subsets are associated with ARDS.