title: Identification of HLA-A24-restricted CD8(+) cytotoxic T-cell epitopes derived from mammaglobin-A, a human breast cancer-associated antigen.
abstract: Human breast cancer-associated antigen, mammaglobin-A (Mam-A), potentially offers a novel therapeutic target as a breast cancer vaccine. In this study, we define the CD8(+) cytotoxic T lymphocyte (CTL) response to Mam-A-derived candidate epitopes presented in the context of HLA-A24 (A*2402). HLA-A24 has a frequency of 72% in Japanese, 27% in Asian Indian, and 18% in Caucasian populations. Using a human leukocyte antigen (HLA)-binding prediction algorithm we identified 7 HLA-A24-restricted Mam-A-derived candidate epitopes (MAA24.1-7). Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-A2402 (T2.A24) indicated that MAA24.2 (CYAGSGCPL) and MAA24.4 (ETLSNVEVF) have the highest HLA-A24 binding affinity. Further, 2 CD8(+) CTL cell lines generated in vitro against T2.A24 cells individually loaded with Mam-A-derived candidate epitopes demonstrated significant cytotoxic activity against MAA24.2 and MAA24.4. In addition, the same CD8(+) CTL lines lysed the HLA-A24(+)/Mam-A(+) stable transfected human breast cancer cell lines AU565 and MDA-MB-361. However, these CTLs had no cytotoxicity against HLA-A24(-)/Mam-A(+) and HLA-A24(+)/Mam-A(-) breast cancer cell lines. In summary, our results define HLA-A24-restricted, Mam-A-derived, CD8(+) CTL epitopes that can potentially be employed for Mam-A-based breast cancer vaccine therapy to breast cancer patients with HLA-A24 phenotype.
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Nayan J
authors.initials: NJ
authors.lastname: Sarma
authors.forename: Vijay
authors.initials: V
authors.lastname: Subramanian
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Fleming
authors.forename: William E
authors.initials: WE
authors.lastname: Gillanders
authors.forename: Thallachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D059871:HLA-A24 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D060785:Mammaglobin A / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: D016827:CD8 Antigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D059871:HLA-A24 Antigen; D060785:Mammaglobin A
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