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Identification and translational validation of novel mammaglobin-A CD8 T cell epitopes.

Authors
  • Soysal, S D
  • Muenst, S
  • Kan-Mitchell, J
  • Huarte, E
  • Zhang, X
  • Wilkinson-Ryan, I
  • Fleming, T
  • Tiriveedhi, V
  • Mohanakumar, T
  • Li, L
  • Herndon, J
  • Oertli, D
  • Goedegebuure, S P
  • Gillanders, W E
Type
Published Article
Journal
Breast Cancer Research and Treatment
Publisher
Springer-Verlag
Publication Date
Oct 01, 2014
Volume
147
Issue
3
Pages
527–537
Identifiers
DOI: 10.1007/s10549-014-3129-x
PMID: 25212176
Source
Medline
License
Unknown

Abstract

Mammaglobin-A (MAM-A) is a secretory protein that is overexpressed in 80 % of human breast cancers. Its near-universal expression in breast cancer as well as its exquisite tissue specificity makes it an attractive target for a breast cancer prevention vaccine, and we recently initiated a phase 1 clinical trial of a MAM-A DNA vaccine. Previously, we have identified multiple MAM-A CD8 T cell epitopes using a reverse immunology candidate epitope approach based on predicted binding, but to date no attempt has been made to identify epitopes using an unbiased approach. In this study, we used human T cells primed in vitro with autologous dendritic cells expressing MAM-A to systematically identify MAM-A CD8 T cell epitopes. Using this unbiased approach, we identified three novel HLA-A2-restricted MAM-A epitopes. CD8 T cells specific for these epitopes are able to recognize and lyse human breast cancer cells in a MAM-A-specific, HLA-A2-dependent fashion. HLA-A2(+)/MAM-A(+) breast cancer patients have an increased prevalence of CD8 T cells specific for these novel MAM-A epitopes, and vaccination with a MAM-A DNA vaccine significantly increases the number of these CD8 T cells. The identification and translational validation of novel MAM-A epitopes has important implications for the ongoing clinical development of vaccine strategies targeting MAM-A. The novel MAM-A epitopes represent attractive targets for epitope-based vaccination strategies, and can also be used to monitor immune responses. Taken together these studies provide additional support for MAM-A as an important therapeutic target for the prevention and treatment of breast cancer.

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