title: Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues.
abstract: The Wilms' tumor gene WT1 is overexpressed in most types of leukemias and various kinds of solid tumors, including lung and breast cancer, and participates in leukemogenesis and tumorigenesis. WT1 protein has been reported to be a promising tumor antigen in mouse and human. In the present study, a single amino-acid substitution, M-->Y, was introduced into the first anchor motif at position 2 of the natural immunogenic HLA-A*2402-restricted 9-mer WT1 peptide (CMTWNQMNL; a.a. 235-243). This substitution increased the binding affinity of the 9-mer WT1 peptide to HLA-A*2402 molecules from 1.82 x 10(-5) to 6.40 x 10(-7) M. As expected from the increased binding affinity, the modified 9-mer WT1 peptide (CYTWNQMNL) elicited WT1-specific cytotoxic T lymphocytes (CTL) more effectively than the natural 9-mer WT1 peptide from peripheral blood mononuclear cells (PBMC) of HLA-A*2402-positive healthy volunteers. CTL induced by the modified 9-mer WT1 peptide killed the natural 9-mer WT1 peptide-pulsed CIR-A*2402 cells, primary leukemia cells with endogenous WT1 expression and lung cancer cell lines in a WT1-specific HLA-A*2402-restricted manner. These results showed that this modified 9-mer WT1 peptide was more immunogenic for the induction of WT1-specific CTL than the natural 9-mer WT1 peptide, and that CTL induced by the modified 9-mer WT1 peptide could effectively recognize and kill tumor cells with endogenous WT1 expression. Therefore, cancer immunotherapy using this modified 9-mer WT1 peptide should provide efficacious treatment for HLA-A*2402-positive patients with leukemias and solid tumors.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita City, Osaka 565-0871, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Masaki
authors.initials: M
authors.lastname: Murakami
authors.forename: Tomoki
authors.initials: T
authors.lastname: Masuda
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakano
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakajima
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.forename: Akio
authors.initials: A
authors.lastname: Hiraki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oji
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawakami
authors.forename: Naoki
authors.initials: N
authors.lastname: Hosen
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fujioka
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.forename: Yuki
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Nishida
authors.forename: Momotaro
authors.initials: M
authors.lastname: Asada
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ogawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D015234:HLA-A Antigens / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015234:HLA-A Antigens; D010446:Peptide Fragments; D025721:WT1 Proteins