title: Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs.
abstract: The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8(+) neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8(+) T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 4M86, Baltimore, Maryland 21231, USA. pskim07@gmail.com
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kim
authors.forename: Todd D
authors.initials: TD
authors.lastname: Armstrong
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wolpoe
authors.forename: Vivian
authors.initials: V
authors.lastname: Weiss
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Manning
authors.forename: Lan Qing
authors.initials: LQ
authors.lastname: Huang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Murata
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: R Todd
authors.initials: RT
authors.lastname: Reilly
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D039521:CD11c Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007141:Immunoglobulin Fc Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases