title: Identification and translational validation of novel mammaglobin-A CD8 T cell epitopes.
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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Soysal
authors.forename: S
authors.initials: S
authors.lastname: Muenst
authors.forename: J
authors.initials: J
authors.lastname: Kan-Mitchell
authors.forename: E
authors.initials: E
authors.lastname: Huarte
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: I
authors.initials: I
authors.lastname: Wilkinson-Ryan
authors.forename: T
authors.initials: T
authors.lastname: Fleming
authors.forename: V
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Herndon
authors.forename: D
authors.initials: D
authors.lastname: Oertli
authors.forename: S P
authors.initials: SP
authors.lastname: Goedegebuure
authors.forename: W E
authors.initials: WE
authors.lastname: Gillanders
mesh_terms: D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D060785:Mammaglobin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D015203:Reproducibility of Results; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D060785:Mammaglobin A; D019444:Vaccines, DNA