Glucocorticoid-induced TNFR family-related receptor (GITR)-expression in tumor infiltrating leucocytes (TILs) is associated with the pathogenesis of esophageal adenocarcinomas with and without Barrett's mucosa
Affiliations: [a] Department of General-, Visceral-, Vascular and Pediatric Surgery, University of Wuerzburg Hospital, Wuerzburg, Germany | [b] Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany
Correspondence:
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Corresponding author: Burkhard H. A. von Rahden, MD, Department of General-, Visceral-, Vascular and Pediatric Surgery, University of Wuerzburg Hospital, Oberduerrbacher Strasse 6, 97080 Wuerzburg, Germany. Tel.: +49(0) 931 201 31045; Fax: +49(0) 931 201 31009; E-mail: Rahden_B@chirurgie.uni-wuerzburg.de.
Abstract: Background:Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett’s esophagus (BE) regarded as precancerous lesion. Glucocorticoid-induced TNFR family-related Receptor (GITR)-mediated inflammation of tumor infiltrating leucocytes (TILs) in the tumor microenvironment might play a role during the multistep carcinogenetic process as either tumor promoting factor according to an inflammatory microenvironment or as a feature of anti-tumor activity. Methods:Immunohistochemical analysis of GITR expression was analyzed in esophageal cancer (n=70: 41 EAC with BE, 19 EAC without BE, and n=10 esophageal squamous-cell carcinomas, ESCC), the adenocarcinoma cell line OE-33, and peripheral blood leucocytes (PBLs) of EAC patients, furthermore in biopsies of BE without intraepithelial neoplasia (IN) (n=18). Results were correlated with clinicopathological parameters and five-year survival rates. Immunohistochemical GITR expression results were confirmed on mRNA level (RT-PCR). Results:Quantification showed a significant increase of 25% GITR positive TILs in EAC with BE (p< 0.05) compared to 13% in adjacent BE, 24% in EAC without BE, 14% in ESCC, and 1% in BE without IN. High GITR levels were not significantly associated with clinicopathologic features which may predict worse clinical outcome and had no impact on survival (p= 0.7878). Increased GITR expression of peripheral blood leucocytes (PBLs) in EAC patients was shown on protein level (32%) and confirmed by RT-PCR (3.7-fold difference compared to normal tissue). Conclusions:This study provides for the first time evidence that GITR expression of TILs is associated in the pathogenesis of Barrett’s esophagus. Our findings suggest that GITR-expression of TILs is associated with cancer progression. Its role as either tumor promoting factor %according to an in the inflammatory microenvironment or as a feature of anti-tumor activity and promising target for molecular therapies needs to be substantiated in further investigations.
Keywords: BE, inflammation, carcinogenesis, clinicopathological parameters
