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A5782 - Regulation of Pulmonary Fibrosis by Immune Checkpoint PD-L1
Author Block: Y. Geng, C. J. Liang, D. M. Habiel, A. Coelho, T. Xie, K. Vrishika, N. liu, C. M. Hogaboam, D. Jiang, P. W. Noble; Cedars-Sinai Medical Center, Women’s Guild Lung Institute, Los Angeles, CA, United States.
Idiopathic pulmonary fibrosis (IPF) is caused by abnormal tissue remodeling and scarring in the lung with unknown etiology. Immune checkpoints including PD-L1 (CD274) are regulators for maintaining systemic immune homeostasis and utilized by many cancer cells to escape the surveillance of the immune system. However, the role of PD-L1 in fibroblast effector functions and in lung fibrosis is unknown. Here, we isolated invasive and non-invasive IPF lung fibroblasts using the matrigel invasion assay. Surprisingly, we found that CD274 mRNAs was significantly upregulated in invasive fibroblasts by RNA-seq. We validated this data using qRT-PCR, flow cytometry analysis and single cell western blot. Cell surface expression of PD-L1 was higher on the IPF lung fibroblasts than healthy controls. PD-L1 expression was co-localized with a small portion of PDGFRβ+ lung fibroblasts in IPF lung tissue sections. Knockdown of CD274 in lung fibroblasts inhibited cell growth, cell migration and cell invasion. Flow sorted PD-L1high and PD-L1low expressing lung fibroblasts were injected into NOD-scid-IL2Rγc(-/-) (NSG) mice to investigate the role of PDL1 on fibrosis in vivo. Mice receiving PD-L1high fibroblasts developed more lung fibrosis demonstrated by more diffuse interstitial fibrosis and an increase in hydroxyproline in the lung than the mice receiving PD-L1low fibroblasts. In conclusion, our data suggest that PD-L1 was upregulated on invasive lung fibroblasts and could serve as a novel therapeutic target for pulmonary fibrosis.