Anti-PD-L1 Antibody Alleviate Pulmonary Fibrosis by Inducing Autophagy via Inhibition of the PI3K/Akt/mTOR Pathway

Abstract

Pulmonary fibrosis is a fatal lung disease for which no effective treatment is available. Previous studies have shown that the expression of PD-L1 is significantly increased in pulmonary fibrosis, and that this is related to the occurrence of this disease. However, the underlying mechanism is not clear. To clarify the efficacy and mechanism of an anti-PD-L1 monoclonal antibody as a treatment for pulmonary fibrosis, we conducted histopathological, molecular, and functional analyses in a mouse model of bleomycin-induced pulmonary fibrosis and a cell model of fibrosis induced by TGF-β1. Our results indicate that PD-L1 is highly expressed in the lung fibrosis model. The anti-PD-L1 mAb significantly alleviated bleomycin-induced lung structural disorders and collagen deposition in mice and inhibited the proliferation, migration, activation and extracellular matrix deposition of TGF-β1-induced lung fibroblasts. Interestingly, the anti-PD-L1 mAb could also alleviate the autophagy impairment observed in pulmonary fibrosis. The potential mechanism is through the downregulation of the PI3K/Akt/mTOR signaling pathway. Our study provides evidence of the crucial ability of anti-PD-L1 mAbs to activate autophagy in the context of pulmonary fibrosis, providing a new strategy for the treatment of this disease.

Funding: This work was supported by the Natural Science Foundation of China (81500023), National Natural Science Foundation of Guangdong Province (2017A030313849).

Declaration of Interests: No conflicts of interest, financial or otherwise, are declared by the authors.

Ethics Approval Statement: The animal study was reviewed and approved by the Southern Medical University.

Keywords: Pulmonary fibrosis, Anti-PD-L1 monoclonal antibody, Autophagy, PI3K/AKT/mTOR