Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs

• Published in: The Journal of clinical investigation 2008-05, Vol.118 (5), p.1700-1711
• Main Authors: Kim, Peter S, Armstrong, Todd D, Song, Hong, Wolpoe, Matthew E, Weiss, Vivian, Manning, Elizabeth A, Huang, Lan Qing, Murata, Satoshi, Sgouros, George, Emens, Leisha A, Reilly, R Todd, Jaffee, Elizabeth M
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Cancer Vaccines - immunology; CD11c Antigen - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Line; Dendritic Cells - cytology; Dendritic Cells - immunology; Female; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Immunoglobulin Fc Fragments - immunology; Mice; Mice, Transgenic; Neoplasms - immunology; Neoplasms - pathology; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - immunology; Survival Rate
• ISSN: 0021-9738
• DOI: 10.1172/JCI34333

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.