title: HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells.
abstract: Wilms tumor gene 1 (WT1) is overexpressed in various malignant neoplasms, and has been demonstrated as an attractive target for cancer immunotherapy. We previously reported the identification of a WT1 protein-derived, 16-mer helper peptide WT1332 that could elicit Th1-type CD4+ T-cell response and bind to multiple HLA class II molecules. In this study, we examined the feasibility of adoptive therapy using CD4+ T cells that were transduced an HLA-DPB1*05:01-restricted, WT1332-specific T-cell receptor (TCR). HLA-DPB1*05:01-restricted, WT1332-specific TCR-transduced CD4+ T cells were successfully generated using lentiviral vector and exhibited strong proliferative response and Th1-type cytokine production in response to WT1332 peptide, WT1 protein, or WT1-expressing tumor cell lysate. Furthermore, the WT1332-specific TCR-transduced CD4+ T cells lysed HLA-DPB1*05:01-positive, WT1-expressing human leukemia cells through granzyme B/perforin pathway. Furthermore, stimulation of peripheral blood mononuclear cells with both HLA-A*24:02-restricted cytotoxic T lymphocytes-epitope peptide (modified 9-mer WT1235 peptide, WT1235m) and WT1332 helper peptide in the presence of WT1332-specific TCR-transduced CD4+ T cells strikingly enhanced the induction of WT1235m-specific cytotoxic T lymphocytes. Thus, these results demonstrated the feasibility of immunotherapy based on adoptive transfer of WT1332-specific TCR-transduced CD4+ T cells for the treatment of leukemia.
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuhung
authors.initials: Y
authors.lastname: Lin
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Fujiki
authors.forename: Akiko
authors.initials: A
authors.lastname: Katsuhara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Nao
authors.initials: N
authors.lastname: Aoyama
authors.forename: Satoe
authors.initials: S
authors.lastname: Tanii
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakajima
authors.forename: Naoya
authors.initials: N
authors.lastname: Tatsumi
authors.forename: Soyoko
authors.initials: S
authors.lastname: Morimoto
authors.forename: Taichi
authors.initials: T
authors.lastname: Tamanaka
authors.forename: Sho
authors.initials: S
authors.lastname: Tachino
authors.forename: Naoki
authors.initials: N
authors.lastname: Hosen
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Nishida
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: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D059871:HLA-A24 Antigen / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007938:Leukemia / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D059868:HLA-DP beta-Chains; C538744:HLA-DPB1*05:01 antigen; D011948:Receptors, Antigen, T-Cell; D025721:WT1 Proteins