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Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes

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Abstract

A breast cancer-associated antigen, mammaglobin-A, is specifically expressed in 80% of primary breast tumors. The definition of immune responses against this highly expressed breast cancer-specific antigen should be of great value in the development of new therapeutic strategies for breast cancer. Thus, the purpose of this study was to identify HLA-A2-restricted mammaglobin-A-derived epitopes recognized by CD8+ cytotoxic T lymphocytes (CTL). We identified seven mammaglobin-A-derived candidate epitopes that bind the HLA-A2 molecule (Mam-A2.1-7) by means of a HLA class I-peptide binding computer algorithm from the Bioinformatics & Molecular Analysis Section of the National Institutes of Health. Subsequently, we determined that CD8+ CTLs from breast cancer patients reacted to the Mam-A2.1 (83–92, LIYDSSLCDL), Mam-A2.2 (2–10, KLLMVLMLA), Mam-A2.3 (4–12, LMVLMLAAL), Mam-A2.4 (66–74, FLNQTDETL), and Mam-A2.7 (32–40, TINPQVSKT) epitopes using an IFN-c ELISPOT assay. Interestingly, healthy individuals also showed high reactivity to the Mam-A2.2 epitope. Two CD8+ CTL lines generated in vitro against TAP-deficient T2 cells loaded with the candidate epitopes showed significant cytotoxic activity against the Mam-A2.1-4 epitopes. These CD8+CTL lines recognized a HLA-A2+breast cancer cell line expressing the Mam-A2.1 epitope. In addition, DNA vaccination of HLA-A2+/human CD8+ double-transgenic mice with a DNA construct encoding the Mam-A2.1 epitope and the HLA-A2 molecule induced a significant expansion of epitope-specific CD8+ CTLs that recognize the same HLA- A2+/Mam-A2.1+ breast cancer cell line. In conclusion, these results demonstrate the immunotherapeutic potential of mammaglobin-A for the treatment and prevention of breast cancer.

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Authors and Affiliations

  1. Department of Surgery, Washington University School of Medicine, MO, USA

    André Jaramillo, Kishore Narayanan, Lacey G. Campbell, Nicholas D. Benshoff, Timothy P. Fleming, Jill R. Dietz & T. Mohanakumar

  2. Department of Genetics, Washington University School of Medicine, MO, USA

    Lonnie Lybarger & Ted H. Hansen

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

    Ted H. Hansen & T. Mohanakumar

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  1. André Jaramillo
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  2. Kishore Narayanan
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  3. Lacey G. Campbell
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  9. T. Mohanakumar
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Jaramillo, A., Narayanan, K., Campbell, L.G. et al. Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes. Breast Cancer Res Treat 88, 29–41 (2004). https://doi.org/10.1007/s10549-004-8918-1

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