title: 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.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsutsumi
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0002-5585-4244
authors.initials: H
authors.lastname: Saeki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakashima
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Anatomic Pathology, Pathological Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D015820:Cadherins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: Epithelial-mesenchymal transition; esophageal cancer; immune system; malignant potential; tumor invasion