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Mammaglobin-A cDNA vaccination of breast cancer patients induces antigen-specific cytotoxic CD4+ICOShi T cells

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Abstract

Mammaglobin-A (Mam-A) is a 10 kDa secretory protein that is overexpressed in 80 % of primary and metastatic human breast cancers. Previous studies from our laboratory demonstrated that Mam-A cDNA vaccine can induce Mam-A-specific CD8 T cell responses and mediate regression of human breast cancer xenografts in NOD/SCID mice. In this article, we present our results on a phase I clinical trial of a Mam-A cDNA vaccination in breast cancer patients with stage-IV metastatic disease, including the impact of vaccination on the expression of the inducible co-stimulator molecule (ICOS) on CD4 T cells. Specimens from seven patients with stage-IV metastatic cancer were available for these analyses. Patients were vaccinated with a Mam-A cDNA vaccine on days 0, 28, and 56, and immune responses were assessed at serial time points following vaccination. At 6 months following the first vaccination, flow cytometric analysis demonstrated a significant increase in the frequency of CD4+ICOShi T cells from 5 ± 2 % pre-vaccination to 23 ± 4 % (p < 0.001), with a concomitant decrease in the frequency of CD4+FoxP3+ T cells (regulatory T cells [Treg]) from 19 ± 6 to 10 ± 5 % (p < 0.05). ELISpot analysis of CD4+ICOShi sorted T cells demonstrated that following vaccination the cytokines produced by Mam-A-specific T cells switched from IL-10 (78 ± 21 spm pre-vaccination to 32 ± 14 spm 5 months post-vaccine p < 0.001) to IFN-γ (12 ± 6 spm pre-vaccination to 124 ± 31 spm 5 months post-vaccine p < 0.001). The ratio of CD4+ICOShi T cells to CD4+FoxP3+ T cells increased from 0.37 ± 0.12 before vaccination to 2.3 ± 0.72 (p = 0.021) following vaccination. Further, these activated CD4+ICOShi T cells induced preferential lysis of human breast cancer cells expressing Mam-A protein. We conclude that Mam-A cDNA vaccination is associated with specific expansion and activation of CD4+ICOShi T cells, with a concomitant decrease in Treg frequency. These encouraging results strongly suggest that Mam-A cDNA vaccination can induce antitumor immunity in breast cancer patients.

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Abbreviations

APCs:

Antigen presenting cells

ICOS:

Inducible co-stimulatory molecule

Mam-A:

Mammaglobin-A

mAb:

Monoclonal antibody

PBMCs:

Peripheral blood mononuclear cells

Treg:

Regulatory T cells

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Acknowledgments

The authors would like to thank Ms. Billie Glasscock for her assistance in submitting this manuscript. This project was funded by DOD/CDMRP-BCRP W81XWH-06-1-0677 (WG). TM is funded by the BJC Foundation.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Washington University School of Medicine, Box 8109-3328 CSRB, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA

    Venkataswarup Tiriveedhi, Timothy P. Fleming, Peter S. Goedegebuure, William E. Gillanders & T. Mohanakumar

  2. Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    Michael Naughton, Cynthia Ma, Craig Lockhart & Feng Gao

  3. Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA

    T. Mohanakumar

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  1. Venkataswarup Tiriveedhi
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Correspondence to T. Mohanakumar.

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Tiriveedhi, V., Fleming, T.P., Goedegebuure, P.S. et al. Mammaglobin-A cDNA vaccination of breast cancer patients induces antigen-specific cytotoxic CD4+ICOShi T cells. Breast Cancer Res Treat 138, 109–118 (2013). https://doi.org/10.1007/s10549-012-2110-9

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  • DOI: https://doi.org/10.1007/s10549-012-2110-9

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