Antibody association with HER-2/neu–targeted vaccine enhances CD8+ T cell responses in mice through Fc-mediated activation of DCs
Peter S. Kim, … , R. Todd Reilly, Elizabeth M. Jaffee
Peter S. Kim, … , R. Todd Reilly, Elizabeth M. Jaffee
Published April 8, 2008
Citation Information: J Clin Invest. 2008;118(5):1700-1711. https://doi.org/10.1172/JCI34333.
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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

Peter S. Kim, Todd D. Armstrong, Hong Song, Matthew E. Wolpoe, Vivian Weiss, Elizabeth A. Manning, Lan Qing Huang, Satoshi Murata, George Sgouros, Leisha A. Emens, R. Todd Reilly, Elizabeth M. Jaffee

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Figure 1

The Fc portion of the intact 7.16.4 mAb is required for enhancement of the vaccine-induced antitumor response.

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The Fc portion of the intact 7.16.4 mAb is required for enhancement of t...
(A) Binding of F(ab′)2 fragments of 7.16.4 (dashed line) were confirmed by flow cytometry, using secondary antibodies specific for the Fc portion and λ1, λ2, and λ3 light chains. Shown are the intact antibody (solid line) and control IgG (gray histogram). (B) Antibody-mediated enhancement of the vaccine-induced antitumor response is not seen in the vaccine + F(ab′)2 treatment group. neu-N mice received neu-targeted vaccine (3T3 neu/GM) or control vaccine (3T3 NP/GM), followed 2 weeks later by NT2 challenge + intact 7.16.4 mAb, + 7.16.4 F(ab′)2, + or irrelevant IgG. The intact and control antibodies were administered weekly for a total of 5 injections (100 μg of IgG per injection). F(ab′)2 fragments were injected twice per week for a total of 10 injections [150 μg of F(ab′)2 per injection]. Survival curves are shown (n = 5 per group). Statistical differences in survival among data groups were assessed using the log-rank test. This experiment was repeated once. (C) Tumor-specific CD8+ T cell responses were not increased in the vaccine + F(ab′)2 treatment group when compared with the vaccine plus intact antibody treatment group. CD8+ T cells were incubated with NT2/B7-1 target cells overnight at 37°C at 5% CO2. IFN-γ ELISPOTs were counted on the next day. Each experiment was repeated 3 times independently. *P < 0.05 versus intact 7.16.4 mAb + neu-targeted vaccine, Mann-Whitney U test.