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

Abstract

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 ZEB1, 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 ZEB1 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. ZEB1 and PD‐L1 expression was determined in TE8 cells, which demonstrate the EMT phenotype, following ZEB1 knockdown by siZEB1. TE5, TE6 and TE11 cells with non‐EMT phenotype were also used for studies of TGF‐β1‐dependent EMT induction and ZEB1 and PD‐L1 expression. In cases of high PD‐L1 expression at the invasive front, significantly greater depth of tumor invasion, EMT, and less CD8+ 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 ZEB1 expression. In TE8 cells, siZEB1 suppressed PD‐L1 and promoted E‐cadherin mRNA and protein expression. TGF‐β1 induced EMT and surface expression of PD‐L1 in TE5, TE6 and TE11 cell lines. PD‐L1 expression at the ESCC invasive front was related to ZEB1 expression, EMT and poor prognosis. We suggest that a cooperative mechanism bridging between tumor immune avoidance and EMT contributes to tumor malignancy in ESCC.

The prognostic impact of programmed cell death 1 and its ligand and the correlation with epithelial‐mesenchymal transition in thymic carcinoma

“…Moreover, our results suggest that EMT status is strongly related with the PD‐L1 expression in TC. In other malignancies such as NSCLC, several groups and our group previously reported a significant relationship between the EMT status and PD‐L1 expression . PD‐L1 expression is regulated by the TGF‐β pathway and the EMT process.…”

“…In other malignancies such as NSCLC, several groups and our group previously reported a significant relationship between the EMT status and PD-L1 expression. 12,24,25 PD-L1 expression is regulated by the TGF-β pathway and the EMT process. Moreover, EMT is regulated by several stimuli.…”

High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer

“…It is well known that a high density of tumor‐infiltrating lymphocytes (TILs) in cancer tissues is associated with improved therapeutic responses and favorable overall survival in esophageal cancer . PD‐1 ligand (PD‐L1) expressed on cancer cells suppresses the cytotoxic activity of TILs, however, and high expression of PD‐L1 on cancer cells was shown to be involved in microenvironmental immune suppression and worse clinical course in patients with esophageal cancer . Combined analyses of TIL density and PD‐L1 expression revealed that esophageal cancer patients with a low density of TILs and high expression of PD‐L1 exhibit a worse clinical course .…”

“…[6][7][8] PD-1 ligand (PD-L1) expressed on cancer cells suppresses the cytotoxic activity of TILs, however, and high expression of PD-L1 on cancer cells was shown to be involved in microenvironmental immune suppression and worse clinical course in patients with esophageal cancer. 9,10 Combined analyses of TIL density and PD-L1 expression revealed that esophageal cancer patients with a low density of TILs and high expression of PD-L1 exhibit a worse clinical course. 11 Many researchers have thus begun to focus on the significance of immune responses in the esophageal cancer microenvironment.…”

ANXA10 induction by interaction with tumor‐associated macrophages promotes the growth of esophageal squamous cell carcinoma

“…Even in superficial esophageal cancers invading no further than the submucosa, 30%–40% of the cases have regional lymph node metastasis . Tobacco use and alcohol consumption are known to contribute to a high risk of ESCC and genetic polymorphisms including ALDH2 , CCND1 , PTEN and PD‐L1 have been identified as risks for ESCC …”