Abstract
Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model. We differentiated hiPSDCs from iPSCs of three healthy donors and transduced CEA cDNA into the hiPSDCs. The surface marker expression, cytokine secretion and migratory capacity of the hiPSDCs were equivalent to those of human monocyte-derived DCs (hMoDCs). Cytotoxic T cells activated by hiPSDCs-CEA exhibited CEA-specific cytotoxic activity against the target cells expressing CEA. Furthermore, in the CEA transgenic mouse model, cytotoxic T cells activated in mice immunized with miPSDCs-CEA displayed CEA-specific cytotoxic activity against MC38-CEA. In the subcutaneous tumour model, vaccination with miPSDCs-CEA achieved a significant growth inhibitory effect on MC38-CEA. No adverse events caused by the administration of miPSDCs were observed. Genetic modification of iPSDCs, inducing the expression of CEA, is a promising tool for clinical applications of vaccine therapy for treating gastrointestinal cancer patients.
Highlights
The clinical application of dendritic cell (DC) vaccine therapy, is hindered by the need for a large quantity of DCs generated from the peripheral blood monocytes of the patient
Flow cytometric analysis demonstrated that mature human iPSDCs (hiPSDCs) expressed a high level of CD209 and DEC205, which were characteristic markers for dendritic cells, the immature hiPSDCs expressed a low level of CD209 and DEC205
In this study using healthy volunteers, cytotoxic T cells induced by in vitro stimulation with hiPSDCs transduced with the full-length Carcinoembryonic antigen (CEA) gene exhibited CEA-specific cytotoxicity against autologous lymphoblastoid cells (LCLs) and HLA-restrictive gastrointestinal cancer cell lines naturally expressing CEA
Summary
The clinical application of DC vaccine therapy, is hindered by the need for a large quantity of DCs generated from the peripheral blood monocytes of the patient. TAA-specific cytotoxic T cells were generated by the administration of genetically modified iPSDCs expressing TAA in a mouse melanoma model[16] This new method may be promising for future clinical applications in cancer immunotherapy. No studies have yet examined the induction of cytotoxic T cells against gastrointestinal tumours by vaccination with iPSDCs. Carcinoembryonic antigen (CEA) is a heavily glycosylated oncofetal antigen overexpressed in human adenocarcinomas, in gastrointestinal cancer, making it a valuable target for immunotherapy specific for gastrointestinal cancer[17,18,19,20]. We transduced mouse iPSDCs (miPSDCs) with the CEA gene and examined whether these genetically modified DCs could induce strong therapeutic antitumor immune responses against tumour cells expressing CEA in CEA transgenic mice.
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