Exosomes of Epstein-Barr Virus-Associated Gastric Carcinoma Suppress Dendritic Cell Maturation

Abstract

The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells.

Exosomes Promote Pre-Metastatic Niche Formation in Gastric Cancer

“…Epstein-Barr virus (EBV)-positive gastric cancer is characterized by an abundance of infiltrated-immune cells, including dendritic cells, but with suppressed anti-tumor immunity. Hinata et al revealed that EBV-positive gastric cancer has more TDE secretion than EBV-negative gastric cancer (58). These TDEs suppress dendritic cell maturation, represented with low CD86 expression, and inhibit activation of other immune cells (58).…”

“…Hinata et al. revealed that EBV-positive gastric cancer has more TDE secretion than EBV-negative gastric cancer ( 58 ). These TDEs suppress dendritic cell maturation, represented with low CD86 expression, and inhibit activation of other immune cells ( 58 ).…”

Special Issue: Epstein–Barr–Virus–Associated Cancers

“…This Special Issue assembles eleven papers, comprising seven research articles, two reviews, and two brief reports, which collectively provide novel information on the mechanisms of oncogenesis [ 2 , 3 , 4 , 5 , 6 ] and viral replication [ 7 , 8 , 9 , 10 ], as well as applications for diagnosis [ 11 , 12 ].…”

“…Using a variety of methods and approaches, several studies have provided a novel notion in understanding how EBV contributes to the development of various tumors, including GC [ 2 , 3 ], HL [ 4 ], NPC [ 5 ], and oral squamous cell carcinoma [ 6 ], on a molecular basis. A distinct feature of EBV-associated GC is the significant infiltration of immune cells in the epithelium, which appears to establish a unique tumor microenvironment.…”

“…A distinct feature of EBV-associated GC is the significant infiltration of immune cells in the epithelium, which appears to establish a unique tumor microenvironment. A study demonstrated that exosomes induce the suppression of maturation of infiltrated dendritic cells in EBV-associated GC [ 2 ]. Bioinformatic approaches revealed that an EBV-encoded microRNA, miR-BART17-5p, directly downregulates Kruppel-like factor 2 in EBV-associated GC cells, which subsequently confers an oncogenic phenotype [ 3 ].…”