title: Genetically modified dendritic cells prime autoreactive T cells through a pathway independent of CD40L and interleukin 12: implications for cancer vaccines.
abstract: Genetic immunization through ex vivo transduction of dendritic cells has been suggested as an effective approach to enhance antitumor immunity by activating both CD4+ and CD8+ T cells. Immunizing mice with dendritic cells transduced with an adenovirus expressing the human melanoma antigen glycoprotein 100 (DCAdhgp100) as a cancer vaccine, we demonstrated complete protective immunity and a potent CTL response against melanomas expressing murine glycoprotein 100 in a CD4+ cell-dependent manner. Surprisingly, however, effective tumor rejection was not the result of cooperation between CD4+ and CD8+ T cells. Protective immunity was completely lost when CD4+ cells were depleted immediately before tumor challenge, whereas it was unaffected by removal of CD8+ cells, establishing a principal role for CD4+ cells in the effector phase of tumor rejection. Neither protective immunity nor CTL generation in this model required interleukin 12, in spite of high levels of IFN-gamma secretion by tumor-reactive T cells. Most notably, the DCAdhgp100 vaccine could elicit protective antitumor CD4+ cells in the absence of CD40 ligand, although it does not bypass the need for CD40-mediated signals to generate melanoma-reactive CTLs. Thus, in contrast to the current thinking that the optimal cancer vaccine should include determinants for both CD4+ and CD8+ cells, the potency of the DCAdhgp100 vaccine appears to be a result of its ability to directly prime autoreactive CD4+ cells through a process that does not require interleukin 12 and CD40 signals.
authors.affiliation: Department of Pathology and Molecular Medicine, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Wan
authors.forename: J
authors.initials: J
authors.lastname: Bramson
authors.forename: A
authors.initials: A
authors.lastname: Pilon
authors.forename: Q
authors.initials: Q
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Gauldie
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D003713:Dendritic Cells / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors
chemical_list: D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma