Characterization of the role of CD8+T cells in breast cancer immunity following mammaglobin-A DNA vaccination using HLA-class-I tetramers


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Abstract

IntroductionMammaglobin-A(mam-A) is expressed in over 80% of human breast tumors. We recently reported that mam-A DNA vaccination resulted in breast cancer immunity in a preclinical model. Here we investigated whether mam-A HLA-class-I tetramers could be used to monitor and define the role of CD8+cytotoxic T-lymphocytes(CTL) in mediating breast cancer immunity following mam-A DNA vaccination.Study DesignMam-A DNA vaccination was performed in HLA-A2+huCD8+ transgenic mice. HLA-A2 tetramers carrying the immunodominant mamA2.1 peptide were used to monitor CD8+CTL. Human breast cancer colonies were developed in immunodeficient SCID-beige mice. ELI-SPOT was used to correlate frequency of mamA2.1 tetramer+CD8+T cells and IFN-γ production [spots per million cells (spm)] in human subjects.ResultsVaccination of HLA-A2+huCD8+ mice with mam-A DNA vaccine, but not empty vector, led to the expansion of mamA2.1 tetramer+CD8+T-cells in peripheral blood (<0.5% pre-vaccination compared to >2.0% post-vaccination). CD8+T cells from vaccinated mice specifically lysed UACC-812(HLA-A2+/mam-A+, 25% lysis) but not MDA-MB-415(HLA-A2/mam-A+) or MCF-7(HLA-A2+/mam-A) breast cancer cells. Adoptive transfer of purified CD8+T cells from vaccinated mice into immunodeficient SCID-beige mice with established human breast cancer colonies led to tetramer+CD8+ T-cell infiltration with regression of UACC-812 but not MCF-7 tumors. HLA-A2+ breast cancer patients revealed increased frequency of mamA2.1 tetramer+CD8+ T-cells compared to normal controls (2.86 ± 0.8% vs. 0.71 ± 0.1%, P = 0.01) that correlated with the IFN-γ response to mamA2.1 peptide (48.1 ± 20.9 vs. 2.9 ± 0.8 spm, P = 0.03).ConclusionsCD8+ T-cells are crucial in mediating breast cancer immunity following mam-A DNA vaccination. Mam-A HLA-class-I tetramers can be effectively used to monitor development of CD8+ T-cells following mam-A vaccination.

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