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

Ankit Bharat, Nicholas Benshoff, Timothy P. Fleming, Jill R. Dietz, William E. Gillanders, T. Mohanakumar

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Introduction: Mammaglobin-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 Design: Mam-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. ELISPOT was used to correlate frequency of mamA2.1 tetramer+CD8+T cells and IFN-γ production [spots per million cells (spm)] in human subjects. Results: Vaccination 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). Conclusions: CD8+ 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.

Original languageEnglish
Pages (from-to)453-463
Number of pages11
JournalBreast Cancer Research and Treatment
Volume110
Issue number3
DOIs
StatePublished - Aug 1 2008

Keywords

  • Breast cancer
  • CD8 T cells
  • DNA vaccination
  • HLA class I tetramers
  • Mammaglobin A

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