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Tumor Microenvironment in Esophageal Adenocarcinoma: Innate and Adaptive Immunity Activation in Neoplastic Mucosa
Marco Scarpa*, Melania Scarpa, Andromachi Kotsafti, Stefano Realdon, Bogdan Filip, Matteo Cagol, Rita Alfieri, Tiziana Morbin, Marina Bortolami, Giorgio Battaglia, Ignazio Castagliuolo, Carlo Castoro
Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy
NTRODUCTION: Esophageal adenocarcinoma (EAC) is an increasingly common cancer with a poor prognosis. EAC microenvironment is characterized by lack of cytokines with anti-cancer effect and by high expression of immuno-suppressive factors. The expression of costimulatory molecules CD80 and CD86 in the esophageal cancer tissue is significantly lower than in the mucosa of healthy patients and it is inversely correlated to the expression of TGF-beta1 and IL-10. This may be one of the mechanisms of impaired function of dendritic cells and immune escape of cancer cells in the esophageal cancer. The aim of the study is to investigate the interplay between epithelium and CD8 T cells that characterizes the immune environment of EAC.
PATIENTS & METHODS: Fresh biopsies (n=32) obtained from healthy esophagus, Barrett's esophagus, esophageal dysplasia and adenocarcinoma were analysed by flow cytometry to quantify the expression of CD80 on esophageal epithelial cells and, its receptor CD28 and the lymphocytes activation marker CD38 on CD8 infiltrating lymphocytes.
Mucosa samples from cancer and from healthy esophagus were obtained during esophagectomy from 58 patients affected by EAC and 12 patients affected by squamous cell cancer (SCC). Frozen samples were analysed with Real Time qPCR for innate immunity (Tlr4, Myd88), costimulatory molecules (Cd80, Cd86), and lymphocytes activation (Cd38, Cd69) genes expression. Immunohistochemistry for CD8 and NK cells cytolytic activity (CD107a) of tumor infiltrating lymphocytes and for CD80 was performed.
Non parametrical statistics was used.
RESULTS: Flow cytometric analysis revealed a significant increase of CD80+ esophageal epithelial cells in metaplasia during inflammatory esophageal carcinogenesis. Moreover, Real Time qPCR showed a significant upregulation of Tlr4, MyD88, Cd80, Cd86, Cd38 and Cd69 gene expression in EAC tissues compared to their matched normal tissues. CD80, CD8 and CD107a proteins expression was higher in the cancer tissue of patient who underwent neoadjuvant therapy. Finally, the number of intraepithelial CD107a+ cells resulted inversely correlated with tumor differentiation and Mandard tumor regression grade.
CONCLUSION: In inflammation-driven esophageal carcinogenesis there is evidence of an early active immune surveillance process mediated by CD80 overexpression on metaplastic esophageal epithelial cells. Overall, EAC microenvironment shows an inflamed phenotype characterized by the presence of functionally inhibited CD8+ T-cells. Notably, patients who underwent neoadjuvant CT-RT show an increased tumor infiltration of degranulating (CD107+) CD8+ and NK cells.
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