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-gamma 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-gamma 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.
INTRODUCTION:Mammaglobin-A(mam-A) is expressed in over 80% of humanbreast 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. Humanbreast cancer colonies were developed in immunodeficient SCID-beige mice. ELISPOT was used to correlate frequency of mamA2.1 tetramer(+)CD8(+)T cells and IFN-gamma 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 humanbreast cancer colonies led to tetramer(+)CD8(+ )T-cell infiltration with regression of UACC-812 but not MCF-7 tumors. HLA-A2(+) breast cancerpatients 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-gamma 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.
Authors: Venkataswarup Tiriveedhi; Natalia Tucker; John Herndon; Lijin Li; Mark Sturmoski; Matthew Ellis; Cynthia Ma; Michael Naughton; A Craig Lockhart; Feng Gao; Timothy Fleming; Peter Goedegebuure; Thalachallour Mohanakumar; William E Gillanders Journal: Clin Cancer Res Date: 2014-12-01 Impact factor: 12.531
Authors: Lijin Li; John M Herndon; Steven M Truscott; Ted H Hansen; Timothy P Fleming; Peter Goedegebuure; William E Gillanders Journal: Vaccine Date: 2010-02-23 Impact factor: 3.641
Authors: Venkataswarup Tiriveedhi; Timothy P Fleming; Peter S Goedegebuure; Michael Naughton; Cynthia Ma; Craig Lockhart; Feng Gao; William E Gillanders; T Mohanakumar Journal: Breast Cancer Res Treat Date: 2012-06-08 Impact factor: 4.872
Authors: S D Soysal; S Muenst; J Kan-Mitchell; E Huarte; X Zhang; I Wilkinson-Ryan; T Fleming; V Tiriveedhi; T Mohanakumar; L Li; J Herndon; D Oertli; S P Goedegebuure; W E Gillanders Journal: Breast Cancer Res Treat Date: 2014-09-12 Impact factor: 4.872