title: Multiple antigen-targeted immunotherapy with alpha-galactosylceramide-loaded and genetically engineered dendritic cells derived from embryonic stem cells.
abstract: Numerous tumor-associated antigens (TAA) have been identified and their use in immunotherapy is considered to be promising. For TAA-based immunotherapy to be broadly applied as standard anticancer medicine, methods for active immunization should be improved. In the present study, we demonstrated the efficacy of multiple TAA-targeted dendritic cell (DC) vaccines and also the additive effects of loading alpha-galactosylceramide to DC using mouse melanoma models. On the basis of previously established methods to generate DC from mouse embryonic stem cells (ES-DC), 4 kinds of genetically modified ES-DC, which expressed the melanoma-associated antigens, glypican-3, secreted protein acidic and rich in cysteine, tyrosinase-related protein-2, or gp100 were generated. Anticancer effects elicited by immunization with the ES-DC were assessed in preventive and also therapeutic settings in the models of peritoneal dissemination and spontaneous metastasis to lymph node and lung. The in vivo transfer of a mixture of 3 kinds of TAA-expressing ES-DC protected the recipient mice from melanoma cells more effectively than the transfer of ES-DC expressing single TAA, thus demonstrating the advantage of multiple as compared with single TAA-targeted immunotherapy. Loading ES-DC with alpha-galactosylceramide further enhanced the anticancer effects, suggesting that excellent synergic effects of TAA-specific cytotoxic T lymphocytes and natural killer T cells against metastatic melanoma can be achieved by using genetically modified ES-DC. With the aid of advancing technologies related to pluripotent stem cells, induced pluripotent stem cells, and ES cells, clinical application of DC highly potent in eliciting anticancer immunity will be realized in the near future.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Motomura
authors.forename: Daiki
authors.initials: D
authors.lastname: Fukuma
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Matsunaga
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ikuta
authors.forename: Tokunori
authors.initials: T
authors.lastname: Ikeda
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kageshita
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D053595:Embryonic Stem Cells / Q000276:immunology; D005699:Galactosylceramides / Q000276:immunology; D005818:Genetic Engineering; D053673:Glypicans / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016233:Immunotherapy, Active; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D015676:Osteonectin / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D005699:Galactosylceramides; D053673:Glypicans; D008562:Membrane Glycoproteins; D015676:Osteonectin; C548637:PMEL protein, human; C548642:Pmel protein, mouse; C493154:alpha-galactosylceramide; D058951:gp100 Melanoma Antigen; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase