title: Antitumor cytotoxicity induced by bone-marrow-derived antigen-presenting cells is facilitated by the tumor suppressor protein p53 via regulation of IL-12.
abstract: Activated antigen-presenting cells (APC) deliver the three signals cytotoxic T cells require to differentiate into effector cells that destroy the tumor. These comprise antigen, co-stimulatory signals and cytokines. Once these cells have carried out their function, they apoptose. We hypothesized that the tumor suppressor protein, p53, played an important role in generating the antitumor response facilitated by APC. CD11c+APC derived from p53 wild-type (wt) mouse (wt p53) GM-CSF bone marrow cultures (BMAPC) and activated had reduced survival compared to BMAPC from p53 null consistent with p53-mediated apoptosis following activation. There was a lower percentage of antigenic peptide/MHC I complexes on antigen-pulsed p53 null cells suggesting p53 played a role in antigen processing but there was no difference in antigen-specific T cell proliferative responses to these cellsin vivo. In contrast, antigen-specific cytotoxicityin vivowas markedly reduced in response to p53 null BMAPC. When these cells were pulsed with a model tumor antigen and delivered as a prophylactic vaccination, they provided no protection against melanoma cell growth whereas wt BMAPC were very effective. This suggested that p53 might regulate the requisite third signal and, indeed, we found that p53 null BMAPC produced less IL-12 than wt p53 BMAPC and that p53 bound to the promoter region of IL-12. This work suggests that p53 in activated BMAPC is associated with the generation of IL-12 required for the differentiation of cytotoxic immune responses and an effective antitumor response. This is a completely new role for this protein that has implications for BMAPC-mediated immunotherapy.
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago , Dunedin, New Zealand.
authors.forename: Tania L
authors.initials: TL
authors.lastname: Slatter
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Department of Microbiology and Immunology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Department of Microbiology and Immunology, School of Medical Sciences, University of Otago , Dunedin, New Zealand.
authors.forename: Chingwen
authors.initials: C
authors.lastname: Tang
authors.affiliation: Children's Medical Research Institute, University of Sydney , Westmead, Australia.
authors.forename: Hamish G
authors.initials: HG
authors.lastname: Campbell
authors.affiliation: Department of Microbiology and Immunology, School of Medical Sciences, University of Otago , Dunedin, New Zealand.
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Ward
authors.affiliation: Department of Microbiology and Immunology, School of Medical Sciences, University of Otago , Dunedin, New Zealand.
authors.forename: Vivienne L
authors.initials: VL
authors.lastname: Young
authors.affiliation: Children's Medical Research Institute, University of Sydney , Westmead, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Van Ly
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago , Dunedin, New Zealand.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Fleming
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Children's Medical Research Institute, University of Sydney, Westmead, Australia; Maurice Wilkins Center, Auckland, New Zealand.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Braithwaite
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Maurice Wilkins Center, Auckland, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Baird
keywords: Cytotoxic immune response; dendritic cells; interleukin 12; p53 tumor suppressor protein; tumor vaccination