title: Identification of gp100-derived, melanoma-specific cytotoxic T-lymphocyte epitopes restricted by HLA-A3 supertype molecules by primary in vitro immunization with peptide-pulsed dendritic cells.
abstract: The human melanocyte lineage-specific antigen gp100 contains several epitopes recognized by cytotoxic T lymphocytes (CTL). However, most of the epitopes reported to date are HLA-A2.1-restricted. Despite the high frequency of HLA-A2.1 in melanoma patients, effective population coverage requires the identification of epitopes restricted by other frequent HLA alleles. Herein, HLA-A3 binding, gp100-derived synthetic peptides were tested for their capacity to elicit anti-melanoma CTL in vitro using CD8+ T cells from healthy donors as responders and peptide-pulsed autologous dendritic cells as antigen-presenting cells. Of 7 peptides tested, 2 (gp100[9(87)] and gp100[10(86)]) induced CTLs that killed melanoma cell lines expressing HLA-A3 and gp100. Additional MHC-binding studies to various HLA molecules belonging to the HLA-A3 superfamily (HLA-A*1101, -A*3101, -A*3301 and -A*6801) were performed to determine whether these CTL epitopes could further increase potential population coverage. Further experiments indicated that the peptide gp100[9(87)], which bound to HLA-A11 with high affinity, was capable of inducing specific CTLs that killed melanoma cells expressing gp100 and HLA-A11 molecules. Our results indicate that the gp100[9(87)] peptide corresponds to a CTL epitope which may be restricted by either the HLA-A3 or HLA-A11 allele, emphasizing its utility for the design and development of epitope-based therapies for melanoma.
authors.affiliation: Epimmune, Inc., San Diego, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kawashima
authors.forename: V
authors.initials: V
authors.lastname: Tsai
authors.forename: S
authors.initials: S
authors.lastname: Southwood
authors.forename: K
authors.initials: K
authors.lastname: Takesako
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: A
authors.initials: A
authors.lastname: Sette
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D003429:Cross Reactions; D003713:Dendritic Cells / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D059870:HLA-A11 Antigen; D015791:HLA-A3 Antigen / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008562:Membrane Glycoproteins / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D058951:gp100 Melanoma Antigen
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015791:HLA-A3 Antigen; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen