title: Suppression of murine tumour growth through CD8+cytotoxic T lymphocytes via activated DEC-205+dendritic cells by sequential administration of α-galactosylceramide in vivo.
abstract: Cancer immunity is mediated through the effective priming and activation of tumour-specific class I MHC molecule-restricted CD8+cytotoxic T lymphocytes (CTLs). DEC-205+dendritic cells (DCs) can cross-present the epitope(s) of captured tumour antigens associated with class I MHC molecules alongside co-stimulatory molecules to prime and activate tumour-specific CD8+CTLs. Immunosuppressive tolerogenic DCs with reduced co-stimulatory molecules may be a cause of impaired CTL induction. Hepa1-6-1 cells were established from the mouse hepatoma cell line Hepa1-6; these cells grow continuously after subcutaneous implantation into syngeneic C57BL/6 (B6) mice and do not prime CD8+CTLs. In this study, we show that the growth of ongoing tumours was suppressed by activated CD8+CTLs with tumour-specific cytotoxicity through the administration of the glycolipid α-galactosylceramide (α-GalCer), which is a compound known to stimulate invariant natural killer T (iNKT) cells and selectively activate DEC-205+DCs. Moreover, we demonstrated that sequential repetitive intraperitoneal inoculation with α-GalCer every 48 hr appeared to convert tolerogenic DEC-205+DCs into immunogenic DCs with a higher expression of co-stimulatory molecules and a stronger cross-presentation capacity, which primed CTL precursors and induced tumour-specific CD8+CTLs within the tumour environment without activating iNKT cells. These findings provide a new basis for cancer immunotherapy to convert tolerogenic DEC-205+DCs within tumours into immunogenic DCs through the sequential administration of an immuno-potent lipid/glycolipid, and then activated immunogenic DCs with sufficient expression of co-stimulatory molecules prime and activate tumour-specific CD8+CTLs within the tumour to control tumour growth.
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.|Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kogo
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Uchida
authors.affiliation: Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hidemi
authors.identifier: 0000-0003-3283-0845
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage*; D005838:Genotype; D007155:Immunologic Factors / Q000008:administration & dosage*; D007167:Immunotherapy / Q000379:methods*; D016219:Immunotherapy, Adoptive; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects*; D059016:Tumor Microenvironment
chemical_list: D005699:Galactosylceramides; D007155:Immunologic Factors; C493154:alpha-galactosylceramide
keywords: co-stimulatory molecule; cytotoxic T lymphocytes; tumour-infiltrating dendritic cells; tumour-infiltrating lymphocytes; α-galactosylceramide