Dendritic Cells in Barrett's Esophagus Carcinogenesis

Abstract

Barrett's esophagus corresponds to the replacement of the normal esophageal squamous epithelium by a columnar epithelium through a metaplastic process. This tissue remodeling is associated with chronic gastroesophageal reflux and constitutes a premalignant lesion leading to a 30- to 60-fold increase in the risk to evolve into esophageal adenocarcinoma. The present study aimed to investigate a possible immune evasion in Barrett's esophagus favoring esophageal adenocarcinoma development. We demonstrated that myeloid and plasmacytoid dendritic cells are recruited during the esophageal metaplasia-dysplasia-carcinoma sequence, through the action of their chemoattractants, macrophage inflammatory protein 3α and chemerin. Next, we showed that, in contrast to plasmacytoid dendritic cells, myeloid dendritic cells, co-cultured with Barrett's esophagus and esophageal adenocarcinoma cell lines, display a tolerogenic phenotype. Accordingly, myeloid dendritic cells co-cultured with esophageal adenocarcinoma cell lines stimulated regulatory T cell differentiation from naïve CD4(+) T cells. In agreement with those results, we observed that both metaplastic areas and (pre)malignant lesions of the esophagus are infiltrated by regulatory T cells. In conclusion, soluble factors secreted by epithelial cells during the esophageal metaplasia-dysplasia-carcinoma sequence influence dendritic cell distribution and promote tumor progression by rendering them tolerogenic.

Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival

“…We did not only identify a significant increase in FOXP3 + cells in late stage EACs, but also in early stage EACs and prior to malignant mucosal changes. Somja et al also reported a significant increase in FOXP3 + cells during the dysplasia-carcinoma frequency in Barrett's esophagus [29]. Hence, CD4 + CD127 low FOXP3 + cells, which are usually classified as regulatory T cells (T REG ), might contribute to tumor development by suppressing pro-inflammatory cytokines.…”

Increased Expression of Chemerin in Squamous Esophageal Cancer Myofibroblasts and Role in Recruitment of Mesenchymal Stromal Cells

“…Since chemerin is a chemoattractant for NK cells and dendritic cells [14], [16], [19] it has been suggested that loss of chemerin allows tumors to evade the immune defense mechanisms that inhibit tumorigenesis [18], [38], [39]. However, esophageal cells may provide a tolerogenic environment [40] that mitigates the protective effects of chemerin. Moreover, in gastric cancer there is increased plasma chemerin and chemerin stimulates cancer cell invasion in vitro [41].…”

The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells

“…We recently reported increased expression of chemerin in OSC CAMs compared with paired ATMs and demonstrated roles in the recruitment of mesenchymal stromal cells (MSCs) and in their regulated secretion ( Kumar et al , 2014 ; Kumar et al , 2015a ). In addition, increased chemerin expression has been identified in oesophageal adenocarcinoma compared with adjacent Barrett's tissue ( Somja et al , 2013 ). In the present study, we hypothesised that chemerin might also have a role within the oesophageal tumour microenvironment by acting on cancer cells.…”