title: Spontaneous CD4+ T cell responses against TRAG-3 in patients with melanoma and breast cancers.
abstract: The taxol resistance gene TRAG-3 was initially isolated from cancer cell lines that became resistant to taxol in vitro. TRAG-3 is a cancer germline Ag expressed by tumors of different histological types including the majority of melanoma, breast, and lung cancers. In the present study, we report that patients with stage IV melanoma and breast cancers developed spontaneous IFN-gamma-producing CD4+ T cell responses against a single immunodominant and promiscuous peptide epitope from TRAG-3 presented in the context of multiple HLA-DR molecules. The TRAG-3-specific CD4+ T cells and clones were expanded in vitro and recognized not only peptide pulsed APCs but also autologous dendritic cells (DCs) loaded with the TRAG-3 protein. All stage IV melanoma patients with TRAG-3-expressing tumors developed spontaneous CD4+ T cell responses against TRAG-3, demonstrating its strong immunogenicity. None of these patients had detectable IgG Ab responses against TRAG-3. TCRbeta gene usage studies of TRAG-3-specific CD4+ T cell clones from a melanoma patient and a normal donor suggested a restricted TCR repertoire in patients with TRAG-3-expressing tumors. Altogether, our data define a novel profile of spontaneous immune responses to cancer germline Ag-expressing tumors, showing that spontaneous TRAG-3-specific CD4+ T cells are directed against a single immunodominant epitope and exist independently of Ab responses. Because of its immunodominance, peptide TRAG-3(34-48) is of particular interest for the monitoring of spontaneous immune responses in patients with TRAG-3-expressing tumors and for the development of cancer vaccines.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Bratislav
authors.initials: B
authors.lastname: Janjic
authors.forename: Pedro
authors.initials: P
authors.lastname: Andrade
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Wang
authors.forename: Julien
authors.initials: J
authors.lastname: Fourcade
authors.forename: Christine
authors.initials: C
authors.lastname: Almunia
authors.forename: Pavol
authors.initials: P
authors.lastname: Kudela
authors.forename: Adam
authors.initials: A
authors.lastname: Brufsky
authors.forename: Samuel
authors.initials: S
authors.lastname: Jacobs
authors.forename: David
authors.initials: D
authors.lastname: Friedland
authors.forename: Ronald
authors.initials: R
authors.lastname: Stoller
authors.forename: Daniel
authors.initials: D
authors.lastname: Gillet
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Herberman
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
authors.forename: Hassane M
authors.initials: HM
authors.lastname: Zarour
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism
chemical_list: C118809:CSAG2 protein, human; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D007371:Interferon-gamma