Development of new treatment strategy by dendritic cells for combination therapy against gastrointestinal cancers

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In order to develop new treatment strategy against gastrointestinal cancers using dendritic cells, we examined the expressional differences of genes and proteins between esophageal cancer cell lines and normal epithelial cell lines from the esophagus with microarray and representational difference analysis. In identified genes (LAGE-1, MAGE-A1, cyclin D2, etc), we revealed the low expression profile of cyclin D2 in esophageal cancer tissues, compared with normal epithelia. Using methylation-specific PCR, HDAC inhibitor, and demethylation agent, we demonstrated the transcriptional repression and silence of promoter region of cyclin D2 gene. In relation with epigenetic control of tumor specific antigen, chemotherapy also showed induction of tumor specific genes and antitumor immunity. We have reported interaction between apoptotic tumor cells and dendritic cells might relate induction mechanisms of antitumor immunity by chemotherapy. From this point of view, we examined the apoptotic mechanisms of TRAIL (produced by activated dendritic cells) in combination with chemotherapy. Chemotherapy increased death receptor on tumor cells, but increased decoy receptor on normal lymphoid cells. These results showed the protection of normal cells and apoptosis of tumor cells in local accumulation of dendritic cells after chemotherapy. Combination therapy with chemotherapy and dendritic cells will break epigenetic silence of tumors and induce tumor regression and specific antitumor immunity.