Programmed death‐ligand 1 expression at tumor invasive front is associated with epithelial‐mesenchymal transition and poor prognosis in esophageal squamous cell carcinoma

Programmed death‐ligand 1 ( PD ‐L1) plays a crucial role in the host immune system in cancer progression. The gene promoter region of PD ‐L1 also contains a binding site for ZEB 1, a transcription factor related to epithelial‐mesenchymal transition ( EMT ). The purpose of this study was to clarify the relationship between PD ‐L1 and EMT and its clinical importance in esophageal squamous cell carcinoma ( ESCC ). PD ‐L1 and ZEB 1 expression at the tumor invasive front was examined by immunohistochemistry in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy, and their expression and clinicopathological factors were compared. ZEB 1 and PD ‐L1 expression was determined in TE 8 cells, which demonstrate the EMT phenotype, following ZEB 1 knockdown by si ZEB 1. TE 5, TE 6 and TE 11 cells with non‐ EMT phenotype were also used for studies of TGF ‐β1‐dependent EMT induction and ZEB 1 and PD ‐L1 expression. In cases of high PD ‐L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT , and less CD 8 + lymphocyte infiltration were observed. High PD ‐L1 expression was also associated with worse overall and relapse‐free survival. A correlation was observed between PD ‐L1 and ZEB 1 expression. In TE 8 cells, si ZEB 1 suppressed PD ‐L1 and promoted E‐cadherin mRNA and protein expression. TGF ‐β1 induced EMT and surface expression of PD ‐L1 in TE 5, TE 6 and TE 11 cell lines. PD ‐L1 expression at the ESCC invasive front was related to ZEB 1 expression, EMT and poor prognosis. We suggest that a cooperative mechanism bridging between tumor immune avoidance and EMT contributes to tumor malignancy in ESCC .