Aging exacerbates checkpoint inhibitor pathway dysfunction in pulmonary fibrosis 3852

Abstract Description Alveolar epithelial type 2 (AT2) cell reprogramming and senescence are hallmarks of pulmonary fibrosis (PF), a parenchymal lung disease more prevalent in aging individuals. We hypothesized that the PD-1/PD-L1 pathway, critical to immunosurveillance of many tissue niches, is exploited by fibrogenic AT2 to promote their persistence during fibrogenesis, worsening disease outcomes. In a clinically relevant, mouse model of spontaneous PF, aged (18-month) mice displayed a worse disease phenotype versus younger (3-month) cohorts characterized by increased weight loss, mortality, BALF cell counts and collagen burden accompanied by higher expression of senescence (Cdnkn1a; Cdnkn2a) and inflammatory (Ccl2; Tnfa) markers. Flow cytometry demonstrated increased accumulation of a CD51+, transitional AT2 population in older mice marked by enhanced PD-L1 levels. Additionally, lungs from older mice demonstrated increases in CD8+ and CD8+PD1+ T cells. Treatment of fibrotic aged mice with a PD-1/PD-L1 inhibitor (BMS-202) resulted in significantly reduced mortality along with decreases in BAL Sircol and improved static lung compliance. These findings suggests that aged mice exhibit a more severe fibrotic phenotype accompanied by alterations in re-programmed AT2 cell numbers and enhanced PD-1/PD-L1 synapses. We propose a model wherein pro-fibrotic epithelial populations escape immune surveillance avoiding clearance by CD8+PD1+ T cells to promote a fibrogenic niche. Funding Sources U01 HL152970 Topic Categories Immune Mechanisms of Human Disease (HUM)