BACKGROUND: A novel breast cancer-associated antigen, mammaglobin-A, is expressed in 80% of primary breast tumors. The characterization of immune responses against this highly expressed breast cancer-specific antigen would be of value in the development of new therapeutic strategies for breast cancer. METHODS: We developed an in vivo model using human leukocyte antigen-A*0201/human CD8+ (HLA-A2+/hCD8+) double-transgenic mice to define the epitopes and to study the level of protection acquired by mammaglobin-A cDNA vaccination toward mammaglobin-A+/HLA-A2+ breast cancer cell lines. Mammaglobin-A epitopes were identified using an HLA class I peptide binding prediction computer program, and their activity was verified using gamma interferon ELISPOT and cytotoxicity assays. RESULTS: We identified seven mammaglobin-A-derived candidate epitopes that bind the HLA-A*0201 molecule (Mam-A2.1-7). CD8+ cytotoxic T lymphocytes (CTLs) from HLA-A2+/hCD8+ mice reacted to the Mam-A2.1 (amino acids [aa] 83-92, LIYDSSLCDL), Mam-A2.2 (aa 2-10, KLLMVLMLA), Mam-A2.4 (aa 66-74, FLNQTDETL), and Mam-A2.6 (aa 32-40, MQLIYDSSL) epitopes. CD8+ CTLs from breast cancer patients also recognized a similar epitope pattern as did those in the HLA-A2+/hCD8 mice and reacted to the Mam-A2.1, Mam-A2.2, Mam-A2.3, Mam-A2.4, and Mam-A2.7 epitopes. Passive transfer of mammaglobin-A-reactive CTLs into SCID (severe combined immunodeficient) beige mice with actively growing mammaglobin-A+ tumors resulted in statistically significant regression (P<.001) in the growth of the tumors. CONCLUSIONS: The HLA-A2+/hCD8+ mouse represents a valuable animal model to characterize the HLA-A*0201-restricted CD8+ CTL immune response to mammaglobin-A in vivo, and the data reported here demonstrate the immunotherapeutic potential of mammaglobin-A for the treatment and/or prevention of breast cancer.
BACKGROUND: A novel breast cancer-associated antigen, mammaglobin-A, is expressed in 80% of primary breast tumors. The characterization of immune responses against this highly expressed breast cancer-specific antigen would be of value in the development of new therapeutic strategies for breast cancer. METHODS: We developed an in vivo model using human leukocyte antigen-A*0201/humanCD8+ (HLA-A2+/hCD8+) double-transgenic mice to define the epitopes and to study the level of protection acquired by mammaglobin-A cDNA vaccination toward mammaglobin-A+/HLA-A2+ breast cancer cell lines. Mammaglobin-A epitopes were identified using an HLA class I peptide binding prediction computer program, and their activity was verified using gamma interferon ELISPOT and cytotoxicity assays. RESULTS: We identified seven mammaglobin-A-derived candidate epitopes that bind the HLA-A*0201 molecule (Mam-A2.1-7). CD8+ cytotoxic T lymphocytes (CTLs) from HLA-A2+/hCD8+ mice reacted to the Mam-A2.1 (amino acids [aa] 83-92, LIYDSSLCDL), Mam-A2.2 (aa 2-10, KLLMVLMLA), Mam-A2.4 (aa 66-74, FLNQTDETL), and Mam-A2.6 (aa 32-40, MQLIYDSSL) epitopes. CD8+ CTLs from breast cancerpatients also recognized a similar epitope pattern as did those in the HLA-A2+/hCD8 mice and reacted to the Mam-A2.1, Mam-A2.2, Mam-A2.3, Mam-A2.4, and Mam-A2.7 epitopes. Passive transfer of mammaglobin-A-reactive CTLs into SCID (severe combined immunodeficient) beige mice with actively growing mammaglobin-A+ tumors resulted in statistically significant regression (P<.001) in the growth of the tumors. CONCLUSIONS: The HLA-A2+/hCD8+ mouse represents a valuable animal model to characterize the HLA-A*0201-restricted CD8+ CTL immune response to mammaglobin-A in vivo, and the data reported here demonstrate the immunotherapeutic potential of mammaglobin-A for the treatment and/or prevention of breast cancer.
Authors: Haseeb Ilias Basha; Venkataswarup Tiriveedhi; Timothy P Fleming; William E Gillanders; T Mohanakumar Journal: Breast Cancer Res Treat Date: 2010-06-11 Impact factor: 4.872
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