title: Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen.
abstract: Using dendritic cells (DCs) electroporated with whole RNA isolated from blasts of a patient with acute myeloid leukemia (AML), we were able to generate leukemia-specific cytotoxic T lymphocytes (CTLs) capable of recognizing the leucemic cells. To identify T-cell epitopes mediating lysis of malignant cells, peptides were eluted from the patient's blasts and analyzed by mass spectrometry (LC/MS)-based peptide sequencing. Using this approach, an HLA-A24-binding peptide derived from Bax inhibitor-1 (BI-1), a regulator of apoptosis pathways, was identified as an epitope recognized by the generated CTLs. To further characterize this novel antigenic peptide, CTLs were induced using DCs electroporated with RNA coding for BI-1 or pulsed with the cognate peptide. These CTLs generated from healthy donors in vitro efficiently lysed the patient's blasts as well as other HLA-matched leukemic cells. In conclusion, we identified a BI-1 peptide as a novel immunogenic tumor-associated antigen (TAA) in AML. In vitro induction of BI-1-specific CTLs by RNA transfection or pulsing of DCs with the synthetically generated peptide was a feasible and highly effective method to generate leukemia-specific CTLs. As BI-1 is (over-) expressed in a broad variety of malignancies, it may represent an interesting novel TAA in the context of cancer vaccines.
authors.affiliation: Department of Hematology, Oncology, Rheumatology and Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Schmidt
authors.forename: T
authors.initials: T
authors.lastname: König
authors.forename: A
authors.initials: A
authors.lastname: Bringmann
authors.forename: S
authors.initials: S
authors.lastname: Held
authors.forename: K
authors.initials: K
authors.lastname: von Schwarzenberg
authors.forename: A
authors.initials: A
authors.lastname: Heine
authors.forename: T A W
authors.initials: TA
authors.lastname: Holderried
authors.forename: S
authors.initials: S
authors.lastname: Stevanovic
authors.forename: F
authors.initials: F
authors.lastname: Grünebach
authors.forename: P
authors.initials: P
authors.lastname: Brossart
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D001752:Blast Crisis; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D059871:HLA-A24 Antigen; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D012334:RNA, Neoplasm; C484209:TMBIM6 protein, human; C028388:thymus-leukemia antigens