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

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 5

The neu-expressing, GM-CSF–secreting vaccine given concurrently with the intact 7.16.4 mAb enhances the effector function and proliferation capability of neu-specific CD8+ T cells in vivo.

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The neu-expressing, GM-CSF–secreting vaccine given concurrently with the...
(A) The neu-expressing, GM-CSF–secreting vaccine given concurrently with the intact 7.16.4 mAb increases the number of activated IFN-γ–expressing RNEU420–429-specific CD8+ T cells following treatment. Each neu-N mouse received 2 × 106 Thy1.2 RNEU420–429-specific CD8+ T cells i.v., followed by 1 × 106 3T3 neu/GM or 3T3/GM cells in each limb s.c. and intact 7.16.4 mAb (100 μg), 7.16.4 F(ab′)2 (150 μg), or irrelevant IgG (100 μg) i.p. on day 0. Their spleens and VDLNs were harvested on day 4, and CD8+ T cells were isolated with the Miltenyi CD8a magnetic beads. The isolated CD8+ T cells were then cocultured (1 × 106) with RNEU420–429-pulsed T2Dq (1 × 106) overnight. Thy1.2 RNEU420–429-specific CD8+ T cells were stained for IFN-γ and analyzed by flow cytometry. The mean fluorescent intensity of IFN-γ in Thy1.2 RNEU420–429-specific CD8+ T cells was also measured. Shown is a representative flow cytometric analysis for 1 mouse per group. This study was performed on a total of 3 mice per group per experiment and was repeated once. The statistical analysis is shown in Table 2. *P < 0.05 as determined by the Mann-Whitney U test compared with 3T3 neu/GM + intact 7.16.4 mAb group. (B) The intact 7.16.4 mAb enhances proliferation of adoptively transferred TCR transgenic T cells in vaccinated neu-N mice. CFSE dilution of Thy1.2 RNEU420–429-specific CD8+ T cells was measured by flow cytometry. Shown is a representative flow cytometric analysis of 1 mouse per group. A total of 3 mice per group were analyzed per experiment, and this experiment was repeated once. The statistical analysis is shown in Table 3.