title: T cells reactive with HLA-A*0201 peptides from the histone demethylase JARID1B are found in the circulation of breast cancer patients.
abstract: The nuclear protein PLU-1/JARID1B/KDM5 is widely expressed in breast cancers while showing highly restricted expression in normal adult tissues. To investigate whether JARID1B is a potential target antigen for immunotherapy of breast cancer, we have analyzed the responses of CD8(+) T cells to JARID1B HLA-A*0201 peptides in vitro and used peptide multimers to detect the presence of JARID1B reactive T cells in the circulation of breast cancer patients. Peptides were selected using two web-based algorithms: criteria for inclusion being a high score in both prediction algorithms, and nonhomology with retinoblastoma binding protein-2 (RBP2/JARID1A/KDM5A). A 65-peptide panel was selected and assayed for binding strength by competition assay to obtain the IC(50). The immunogenicity in vitro of these peptides was assessed by T cell stimulation experiments, using autologous dendritic cells as APCs in the first rounds followed by autologous lymphoblasts. Fourteen of the peptides assayed produced cultures having >2% of the CD8(+) cells being IFN-γ(+) after 3-6 rounds of stimulation. An HLA-A*0201 cell line could activate the specific T cells if pulsed with peptide, but endogenous peptide levels were insufficient for activation. Nevertheless, multimer staining of circulating T cells from breast cancer patients showed a significantly higher percentage of multimer positive CD8(+) T cells, as compared to healthy adults for two of three JARID1B epitopes tested. One of these, peptide 73 (QLYALPCVL), was analyzed for memory phenotype, and found to have a significantly higher proportion of central memory T cells than the control group, demonstrating a previous exposure to the peptide.
authors.affiliation: King's College London, Research Oncology, Breast Cancer Biology Group, Bermondsey Wing, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Coleman
authors.forename: Isabel
authors.initials: I
authors.lastname: Correa
authors.forename: Lucienne
authors.initials: L
authors.lastname: Cooper
authors.forename: Hermann R
authors.initials: HR
authors.lastname: Bohnenkamp
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Joy M
authors.initials: JM
authors.lastname: Burchell
authors.forename: Joyce
authors.initials: J
authors.lastname: Taylor-Papadimitriou
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D056466:Histone Demethylases / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D017403:In Situ Hybridization; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000276:immunology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human