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

• Published in: American journal of respiratory cell and molecular biology Vol. 71; no. 5; pp. 534 - 545
• Main Authors: Morrell, Eric D., Holton, Sarah E., Wiedeman, Alice, Kosamo, Susanna, Mitchem, Mallorie A., Dmyterko, Victoria, Franklin, Zoie, Garay, Ashley, Stanaway, Ian B., Liu, Ted, Sathe, Neha A., Mabrey, F. Linzee, Stapleton, Renee D., Malhotra, Uma, Speake, Cate, Hamerman, Jessica A., Pipavath, Sudhakar, Evans, Laura, Bhatraju, Pavan K., Long, S. Alice, Wurfel, Mark M., Mikacenic, Carmen
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.11.2024
• Subjects: Adult; Aged; Alveoli; B7-H1 Antigen - blood; B7-H1 Antigen - metabolism; Bronchoalveolar Lavage Fluid - immunology; Cell activation; Cell survival; Cellular biology; Clinical trials; Cytokines; Cytokines - blood; Cytokines - metabolism; Female; Humans; Immune checkpoint; Inflammation; Lymphocytes T; Male; Middle Aged; Mortality; Original Research; PD-1 protein; PD-L1 protein; Plasma levels; Programmed Cell Death 1 Receptor - metabolism; Pulmonary Alveoli - immunology; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Respiratory distress syndrome; Respiratory Distress Syndrome - blood; Respiratory Distress Syndrome - immunology; Respiratory Distress Syndrome - metabolism; Respiratory tract; respiratory distress syndrome; macrophage; immune checkpoints
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2024-0201OC

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 [  = 59] and ARDS2 [  = 78]) or plasma samples alone (ARDS3 [  = 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 (  = 18) and blood (  = 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 T cells had more intracellular cytokine staining than PD-1 T cells. Subjects without ARDS had a higher ratio of PD-L1 alveolar macrophages to PD-1 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.