title: Cross-reactive CD4+ T cells against one immunodominant tumor-derived epitope in melanoma patients.
abstract: TCRs exhibit a high degree of specificity but may also recognize multiple and distinct peptide-MHC complexes, illustrating the so-called cross-reactivity of TCR-peptide-MHC recognition. In this study, we report the first evidence of CD4(+) T cells recognizing the same tumor peptide-epitope from NY-ESO-1, in the context of multiple HLA-DR and HLA-DP molecules. These cross-reactive CD4(+) T cells recognized not only autologous but also allogenic dendritic cells previously loaded with the relevant protein (i.e., the normally processed and presented epitope). Using clonotypic real-time RT-PCR, we have detected low frequencies of CD4(+) T cells expressing one cross-reactive TCR from circulating CD4(+) T cells of patients with stage IV melanoma either spontaneously or after immunization but not in normal donors. The maintenance of cross-reactive tumor Ag-specific CD4(+) T cells in PBLs of cancer patients required the presence of tumor Ag/epitope in the context of the MHC molecule used to prime the Ag-specific CD4(+) T cells. Our findings have significant implications for the optimization of TCR gene transfer immunotherapies widely applicable to cancer patients.
authors.affiliation: Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Pavol
authors.initials: P
authors.lastname: Kudela
authors.forename: Bratislav
authors.initials: B
authors.lastname: Janjic
authors.forename: Julien
authors.initials: J
authors.lastname: Fourcade
authors.forename: Florence
authors.initials: F
authors.lastname: Castelli
authors.forename: Pedro
authors.initials: P
authors.lastname: Andrade
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Talal
authors.initials: T
authors.lastname: El-Hefnawy
authors.forename: Massimo
authors.initials: M
authors.lastname: Amicosante
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
authors.forename: Hassane M
authors.initials: HM
authors.lastname: Zarour
mesh_terms: D000937:Antigen-Antibody Reactions; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D008545:Melanoma / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000276:immunology; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins