BMS-202, a PD-1/PD-L1 inhibitor, decelerates the pro‑fibrotic effects of fibroblasts derived from scar tissues via ERK and TGFβ1/Smad signaling pathways

Abstract

Introduction: Hypertrophic scar (HS), a fibroproliferative disorder of the skin with some tumor-like properties, is closely related to dysregulated inflammation. PD-1/PD-L1 inhibitor is a promising medication for cancer therapy as its potent functions on adaptive immune response; whether it could be a candidate for HS therapy has aroused our interest. This study aimed to explore the effect and the mechanism of BMS-202, a PD-1/PD-L1 inhibitor, in HS. Methods: Ten HS and adjacent normal skin tissues collected from HS patients were used to detect α-SMA, collagen I, and PD-L1 expression by Quantitative reverse transcription-polymerase chain reaction and western blot (WB) analysis. Fibroblasts derived from HS tissues (HFBs) were exposed to diverse concentrations of BMS-202, of which proliferation, migration, apoptosis, and collagen synthesis were evaluated by Cell Counting Kit-8, wound healing, terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End labeling, and [3H]‑proline incorporation assays, respectively. The effect of BMS-202 on α-SMA and collagen I expression, and transforming growth factor beta 1 (TGFβ1)/Smad signaling in HFBs was also determined by WB and enzyme-linked immunosorbent assay. Results: The expression level of PD-L1 was significantly elevated in both HS tissues and HFBs, which was positively correlated with α-SMA and collagen I expressions. BMS-202 exerted a significant suppression effect on the cell proliferation, migration, collagen synthesis, and α-SMA and collagen I expression of HFBs in a concentration-dependent way; but did not affect apoptosis. Finally, BMS-202 could reduce the phosphorylation of ERK1/2, Smad2, and Smad3, and the TGFβ1 expression once its concentration reached 2.5 nM. Conclusion: BMS-202 effectively suppressed proliferation, migration, and extracellular matrix deposition of HFBs, potentially through the regulation of the ERK and TGFβ1/Smad signaling pathways.