PD-1/PD-L1 enrichment in the IPF lung as a mechanism of senescent cell immune evasion 2266760

Abstract Introduction Idiopathic pulmonary fibrosis (IPF) is an age-related lung disease characterized by the accumulation of senescent cells that deposit extracellular matrix components and soluble proteins, thereby altering the microenvironment. Our previous data indicate a reduced proportion of cytotoxic NK cells in the lungs of patients with IPF. Furthermore, mouse models of lung fibrosis demonstrate that depletion of total NK cells leads to the persistence of senescent cells and exacerbated fibrosis. We postulate that aging and local microenvironmental factors impair the ability of NK cells to eliminate senescent cells. Methods To characterize human IPF cells, single-cell suspensions from lymph nodes and lungs of healthy individuals and IPF patients were analyzed using in vitro cytotoxicity assays, flow cytometry, and single-cell RNA sequencing (scRNA-seq). Results scRNA-seq analysis of lung cell suspensions from healthy and IPF donors revealed that IPF NK cells exhibit reduced expression of cytotoxicity-related genes and increased expression of PD-1, a key regulator of immune cell function. When NK cells were pre-treated with conditioned media from human lung fibroblasts (hLF-CM), only conditioned media derived from IPF fibroblasts induced PD-1 expression in NK cells. Flow cytometry and culture assays further demonstrated that senescent IPF lung fibroblasts express high levels of PD-L1, which in turn suppresses NK cell cytotoxic activity. Conclusion Collectively, our findings suggest that the IPF lung microenvironment modulates NK cell function, promoting the accumulation of pro-fibrotic senescent fibroblasts. These results support the potential use of PD-L1 inhibitors to restore NK cell activity and provide a novel therapeutic strategy for IPF. Funding Source Davis Heart and Lung Research Institute, U01HL145550 Topic Categories Immune Mechanisms of Human Disease (HUM)