PD-L1 Expression in Patients with Idiopathic Pulmonary Fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is the most common and severe form within the group of idiopathic interstitial pneumonias. It is characterized by repetitive alveolar injury in genetically susceptible individuals and abnormal wound healing, leading to dysregulated bronchiolar proliferation and excessive deposition of extracellular matrix, causing complete architectural distortion and fibrosis. Epithelial-to-mesenchymal transition is considered an important pathogenic event, a phenomenon also observed in various malignant neoplasms, in which tumor cells express programmed death-ligand one (PD-L1). The aim of this study was to assess the presence of PD-L1 in patients with IPF and other interstitial lung diseases (ILDs). Method: Patients with a clinically and radiologically suspected idiopathic interstitial pneumonia or other ILDs undergoing transbronchial cryobiopsy to confirm the diagnosis at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, were included in this prospective observational study. Cellular membrane PD-L1 expression in epithelial cells was determined using the DAKO PD-L1 IHC 22C3 PharmDx Kit. Results: Membrane-bound PD-L1 (mPD-L1) was found in twelve (28%) of the forty-three patients with IPF and in five (9%) of the fifty-five patients with other ILDs (p = 0.015). When adjusting for age, gender and smoking status, the odds ratio of having IPF when expressing mPD-L1 in alveolar and/or bronchiolar epithelial cells was 4.3 (CI: 1.3–14.3). Conclusion: Expression of mPD-L1 in epithelial cells in the lung parenchymal zones was detected in a consistent subgroup of patients with IPF compared to other interstitial pneumonias. Larger studies are needed to explore the role of mPD-L1 in patients with IPF.

Lung cancer in patients with fibrosing interstitial lung diseases: an overview of current knowledge and challenges

“…Along with formation of a fibrotic microenvironment [ 38 ], these processes lead to bronchial overgrowth and cancer cell development and progression [ 37 ]. In a subset of IPF patients, expression of membrane PD-L1 protein in alveolar and/or bronchiolar cells was documented, confirming the pathogenetic role of EMT and reinforcing the links between IPF pathogenesis and carcinogenesis [ 43 ].…”

γH2AX, a DNA Double-Strand Break Marker, Correlates with PD-L1 Expression in Smoking-Related Lung Adenocarcinoma

“…Celada et al [ 11 ] demonstrated that CD4+ T cells in fibrosis affected high PD-L1 expression and found that higher PD-L1 expression was shown in idiopathic pulmonary fibrosis (IPF) than in the controls. Kronborg-White et al [ 12 ] also demonstrated upregulation of PD-L1 in pulmonary epithelial cells in IPF patients. Kunwar et al [ 14 ] demonstrated that irradiation induced γH2AX expression and subsequent interstitial fibrosis.…”

“…We proved a positive relation between the expression of γH2AX and PD-L1 in lung adenocarcinomas. For subpopulations of adenocarcinomas, positive correlation was confirmed between γH2AX and PD-L1 in adenocarcinoma without fibrosis with statistical significance in contrast to no association in adenocarcinoma with fibrosis [ 11 , 12 , 13 ]. Celada et al [ 11 ] demonstrated that CD4+ T cells in fibrosis affected high PD-L1 expression and found that higher PD-L1 expression was shown in idiopathic pulmonary fibrosis (IPF) than in the controls.…”

Cell-surface PD-L1 expression identifies a sub-population of distal epithelial cells enriched in idiopathic pulmonary fibrosis

“…Although CD274 expression has been acknowledged in the alveolar and bronchiolar compartments of the IPF lung [24], this is the first study that assesses its cell-surface expression, which is related to its functional immune-suppressive role. In the context of IPF and bleomycin-induced lung fibrosis, CD274 induction plays a role in the SMAD3/GSK3-mediated fibroblast to myofibroblast fate induction and collagen deposition [37][36], and in the IPF fibroblasts’ invasive properties [35][38].…”

“…The presence of these cells is associated with higher fibroblast foci detection and patchy fibrosis compared to patients negative for PD-L1. However, no correlation between the expression of PD-L1 and honeycomb formation could be detected [24]. We also found in the normal human lung a subcluster of AT2 PD-L1 high cells following data mining of the scRNA-seq database [25].…”