title: Melanoma-specific CD4+ T lymphocytes recognize human melanoma antigens processed and presented by Epstein-Barr virus-transformed B cells.
abstract: While much emphasis has been placed on the role of MHC class I-restricted CD8+ T cells in the recognition of tumor-specific antigens (Ag), evidence has accumulated that CD4+ T cells also play a critical role in the anti-tumor immune response. However, little information exists on the nature of MHC class II-restricted human tumor Ag. In an attempt to develop in vitro systems to characterize such Ag, we examined the ability of Epstein-Barr virus (EBV)-transformed B cells to present melanoma-associated Ag to melanoma-specific CD4+ cells. CD4+ T cells cultured from lymphocytes infiltrating a s.c. melanoma metastasis secreted TNF-alpha and GM-CSF specifically in response to autologous cultured melanoma cells expressing MHC class II molecules. These CD4+ cells also recognized MHC class II-compatible EBV-B cells pulsed with extracts of autologous melanoma cells, but failed to recognize EBV-B cells pulsed with autologous non-transformed cells or a variety of allogeneic tumors or normal cells. B cells pre-fixed with paraformaldehyde were incapable of Ag presentation, suggesting that intracellular processing events were occurring. Antibody-blocking studies defined HLA-DR as the dominant if not exclusive restriction locus in this T-B interaction, and HLA-DR genotyping revealed DRBI*0404 to be the probable restriction element. In a second patient, a CD4+ T-cell clone cultured from a melanoma lesion recognized autologous tumor Ag presented by autologous EBV-B; no corss-reactivity was observed with the other tumor system investigated, nor with autologous CD4+ T cells specific for tetanus toxoid. These findings demonstrate that tumor Ag can be processed and presented by EBV-transformed B cells to MHC class II-restricted tumor-specific CD4+ T cells. They also provide a model system for direct identification of these tumor-derived antigens.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: S L
authors.initials: SL
authors.lastname: Topalian
authors.forename: L
authors.initials: L
authors.lastname: Rivoltini
authors.forename: M
authors.initials: M
authors.lastname: Mancini
authors.forename: J
authors.initials: J
authors.lastname: Ng
authors.forename: R J
authors.initials: RJ
authors.lastname: Hartzman
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002472:Cell Transformation, Viral / Q000276:immunology*; D000939:Epitopes; D006680:HLA Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000939:Epitopes; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins