title: Multiple melanoma-associated epitopes recognized by HLA-A3-restricted CTLs and shared by melanomas but not melanocytes.
abstract: The molecular characterization of melanoma-associated Ags allowed the definition of several HLA class I-presented peptides recognized by T cells. However, no HLA-A3.1-restricted melanoma epitopes have been identified to date. To gain insight into the HLA-A3.1-restricted T cell epitope repertoire of human melanoma, we analyzed the immunologic reactivity of CTLs isolated from tumor-involved or tumor-free lymph nodes in two HLA-A3.1+ melanoma patients. Three CTL lines, clonal or highly oligoclonal in their TCR composition, and two CTL clones were selected for HLA class I-restricted lysis of the autologous tumor and then tested for the recognition of HLA-A3+ and HLA-A3- normal or neoplastic cells of the melanocyte lineage. One CTL recognized a unique HLA-A3.1-restricted Ag expressed only by the autologous tumors, while all the other CTLs defined three HLA-A3.1 epitopes shared by melanomas, but not by melanocytes. Moreover, the epitopes of two CTL lines with different specificity were reconstituted by nonoverlapping fractions of HLA-A3+ melanoma-derived peptides resolved by reverse phase-HPLC, indicating that distinct naturally processed peptides were specifically recognized on melanoma cells in association with HLA-A3.1 molecules. These novel lineage-unrelated HLA-A3.1-restricted melanoma epitopes do not derive from MAGE, BAGE, or GAGE gene families, as evaluated by the COS-7 transfection assay. Our data show that CTLs may recognize HLA-A3.1-class 1 complexes presenting melanoma (but not melanocyte)-associated epitopes that are either unique to a given patient's tumor or that are shared between multiple melanomas.
authors.affiliation: Division of Experimental Oncology D, Tumor Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mazzocchi
authors.forename: W J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: C
authors.initials: C
authors.lastname: Traversari
authors.forename: P
authors.initials: P
authors.lastname: Tarsini
authors.forename: M J
authors.initials: MJ
authors.lastname: Maeurer
authors.forename: L
authors.initials: L
authors.lastname: Rivoltini
authors.forename: C
authors.initials: C
authors.lastname: Vegetti
authors.forename: F
authors.initials: F
authors.lastname: Belli
authors.forename: A
authors.initials: A
authors.lastname: Anichini
authors.forename: G
authors.initials: G
authors.lastname: Parmiani
authors.forename: C
authors.initials: C
authors.lastname: Castelli
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D015791:HLA-A3 Antigen / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008544:Melanocytes / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D015791:HLA-A3 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma