title: A novel population of human melanoma-specific CD8 T cells recognizes Melan-AMART-1 immunodominant nonapeptide but not the corresponding decapeptide.
abstract: HLA-A2-restricted cytolytic T cells specific for the immunodominant human tumor Ag Melan-A(MART-1) can kill most HLA-matched melanoma cells, through recognition of two naturally occurring antigenic variants, i.e., Melan-A nonamer AAGIGILTV and decamer EAAGIGILTV peptides. Several previous studies have suggested a high degree of TCR cross-reactivity to the two peptides. In this study, we describe for the first time that some T cell clones are exclusively nonamer specific, because they are not labeled by A2/decamer-tetramers and do not recognize the decamer when presented endogenously. Functional assays with peptides gave misleading results, possibly because decamers were cleaved by exopeptidases. Interestingly, nonapeptide-specific T cell clones were rarely Valpha2.1 positive (only 1 of 19 clones), in contrast to the known strong bias for Valpha2.1-positive TCRs found in decamer-specific clones (59 of 69 clones). Molecular modeling revealed that nonapeptide-specific TCRs formed unfavorable interactions with the decapeptide, whereas decapeptide-specific TCRs productively created a hydrogen bond between CDR1alpha and glutamic acid (E) of the decapeptide. Ex vivo analysis of T cells from melanoma metastases demonstrated that both nonamer and decamer-specific T cells were enriched to substantial frequencies in vivo, and representative clones showed efficient tumor cell recognition and killing. We conclude that the two peptides should be regarded as distinct epitopes when analyzing tumor immunity and developing immunotherapy against melanoma.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.forename: Mathias
authors.initials: M
authors.lastname: Ferber
authors.forename: Cédric
authors.initials: C
authors.lastname: Touvrey
authors.forename: Estelle
authors.initials: E
authors.lastname: Devevre
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Antoine
authors.initials: A
authors.lastname: Leimgruber
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lévy
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell