title: Therapeutic effect of alpha-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells.
abstract: The close cooperation of both innate and acquired immunity is essential for the induction of truly effective antitumor immunity. We tested a strategy to enhance the cross-talk between NKT cells and conventional antigen-specific T cells with the use of alpha GalCer-loaded dendritic cells genetically engineered to express antigen plus chemokine, attracting both conventional T cells and NKT cells. DC genetically engineered to express a model antigen, OVA, along with SLC/CCL21 or monokine induced by IFN-gamma/CXCL9, had been generated using a method based on in vitro differentiation of DC from mouse ES cells. The ES-DC were loaded with alpha-GalCer and transferred to mice bearing MO4, an OVA-expressing melanoma, and their capacity to evoke antitumor immunity was evaluated. In vivo transfer of either OVA-expressing ES-DC, stimulating OVA-reactive T cells, or alpha-GalCer-loaded non-transfectant ES-DC, stimulating NKT cells, elicited a significant but limited degree of protection against the i.p. disseminated MO4. A more potent antitumor effect was observed when alpha-GalCer was loaded to ES-DC expressing OVA before in vivo transfer, and the effect was abrogated by the administration of anti-CD8, anti-NK1.1 or anti-asialo GM1 antibody. alpha-GalCer-loaded double transfectant ES-DC expressing SLC along with OVA induced the most potent antitumor immunity. Thus, alpha-GalCer-loaded ES-DC expressing tumor-associated antigen along with SLC can stimulate multiple subsets of effector cells to induce a potent therapeutic effect against peritoneally disseminated tumor cells. The present study suggests a novel way to use alpha-GalCer in immunotherapy for peritoneally
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Hidetake
authors.initials: H
authors.lastname: Matsuyoshi
authors.forename: Shinya
authors.initials: S
authors.lastname: Hirata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshitake
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Motomura
authors.forename: Daiki
authors.initials: D
authors.lastname: Fukuma
authors.forename: Akari
authors.initials: A
authors.lastname: Kurisaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
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; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D005699:Galactosylceramides / Q000627:therapeutic use*; D005818:Genetic Engineering; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D005699:Galactosylceramides; D011994:Recombinant Proteins; C493154:alpha-galactosylceramide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin