Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes by CD8+ cytotoxic T lymphocytes from breast cancer patients

Andrés Jaramillo, Kishore Narayanan, Lacey G. Campbell, Nicholas D. Benshoff, Lonnie Lybarger, Ted H. Hansen, Timothy P. Fleming, Jill R. Dietz, T. Mohanakumar

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)29-41
Number of pages13
JournalBreast Cancer Research and Treatment
Volume88
Issue number1
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

Keywords

  • CD8+ T lymphocytes
  • HLA-A2
  • epitope
  • mammaglobin-A
  • tumor-specific antigen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Jaramillo, A., Narayanan, K., Campbell, L. G., Benshoff, N. D., Lybarger, L., Hansen, T. H., Fleming, T. P., Dietz, J. R., & Mohanakumar, T. (2004). Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes by CD8+ cytotoxic T lymphocytes from breast cancer patients. Breast Cancer Research and Treatment, 88(1), 29-41. https://doi.org/10.1007/s10549-004-8918-1