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 6

A neu-expressing, GM-CSF–secreting vaccine given concurrently with the intact 7.16.4 mAb promotes the development of RNEU420–429-specific CD8+ TCM.

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A neu-expressing, GM-CSF–secreting vaccine given concurrently with the i...
(A) The intact 7.16.4 mAb increases the total population of RNEU420–429-specific CD8+ T cells with time. Each neu-N mouse received the same treatment protocol as described in Figure 5A, except 4 × 106 Thy1.2+ RNEU420–429-specific CD8+ T cells were used instead of 2 × 106 cells. After 30 days, the mice were boosted with 1 × 106 3T3 neu/GM cells in all 4 limbs. One week after the boost, their spleens and VDLNs were harvested and CD8+ T cells were isolated using the Miltenyi CD8a magnetic beads. The proportion of Thy1.2+ RNEU420–429-specific CD8+ T cells present in the isolated CD8+ T cell population was analyzed by flow cytometry. (B) The intact 7.16.4 mAb enhances proliferation of RNEU420–429-specific CD8+ TCM. Thy1.2+ RNEU420–429-specific CD8+ T cells from the experiment described in A were stained for CD62L and CD44 and analyzed by flow cytometry. Shown is a representative flow cytometric analysis of 1 mouse per group. A total of 3 mice per group were analyzed, and this study was repeated once. The gating represents Thy1.2+ CD8+ T cells. *P < 0.05 versus intact 7.16.4 mAb + neu-targeted vaccine, Mann-Whitney U test.