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

IntroductionHypertrophic 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.MethodsTen 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.ResultsThe 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.ConclusionBMS‐202 effectively suppressed proliferation, migration, and extracellular matrix deposition of HFBs, potentially through the regulation of the ERK and TGFβ1/Smad signaling pathways.