title: Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor.
abstract: Wilms' tumor gene WT1 is highly expressed in leukemia and in various types of solid tumors and exerts an oncogenic function. Thus, WT1 protein is a most promising tumor-associated antigen. We have been successfully performing WT1 vaccination with a 9-mer modified WT1(235) peptide, which has one amino acid substitution (M→Y) at position 2 of 9-mer natural WT1(235) peptide (235-243 a.a.), for close to 700 HLA-A*24:02-positive patients with leukemia or solid tumors. Although vaccination of modified WT1(235) peptide induced natural WT1(235) peptide-recognizing cytotoxic T-lymphocytes (CTLs) and exerted cytotoxic activity towards leukemia and solid tumor cells that expressed the natural WT1(235) peptide (epitope) but not the vaccinated modified WT1(235) peptide (epitope), the molecular basis has remained unclear. In this study, we established a modified WT1(235) peptide-specific CTL clone, we isolated T-cell receptor (TCR) genes from it and transduced the TCR genes into CD8(+) T-cells. The TCR-transduced CD8(+) T-cells produced interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) in response to stimulation not only with the modified WT1(235) peptide but also with the natural WT1(235) peptide and lysed modified or natural WT1(235) peptide-pulsed target cells and endogenously WT1-expressing leukemia cells in a HLA-A*24:02-restriction manner. These results provided us, for the first time at molecular basis, with a proof-of-concept of modified WT1(235) peptide-based immunotherapy for natural WT1(235) peptide-expressing malignancies.
authors.affiliation: Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Tamanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Fujiki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Akiko
authors.initials: A
authors.lastname: Katsuhara
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakajima
authors.forename: Naoki
authors.initials: N
authors.lastname: Hosen
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Nishida
authors.forename: Yu-Hung
authors.initials: YH
authors.lastname: Lin
authors.forename: Sho
authors.initials: S
authors.lastname: Tachino
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akatsuka
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oji
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D002999:Clone Cells; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D057809:HEK293 Cells; D059871:HLA-A24 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy; D009842:Oligopeptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D014162:Transfection; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: C542271:CMTWNQMNL peptide; D019496:Cancer Vaccines; D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D025721:WT1 Proteins