Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor

Tamanaka Taichi, Yoshihiro Oka, Fumihiro Fujiki, Akihiro Tsuboi, Akiko Katsuhara, Hiroko Nakajima, Naoki Hosen, Sumiyuki Nishida, Yu Hung Lin, Sho Tachino, Yoshiki Akatsuka, Kiyotaka Kuzushima, Yusuke Oji, Atsushi Kumanogoh, Haruo Sugiyama

Research output: Contribution to journalArticle

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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 WT1235peptide, which has one amino acid substitution (M→Y) at position 2 of 9-mer natural WT1235 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 WT1235 peptide-recognizing cytotoxic T-lymphocytes (CTLs) and exerted cytotoxic activity towards leukemia and solid tumor cells that expressed the natural WT1235 peptide (epitope) but not the vaccinated modified WT1235 peptide (epitope), the molecular basis has remained unclear. In this study, we established a modified WT1235 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 WT1235 peptide but also with the natural WT1235 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 WT1235 peptide-based immunotherapy for natural WT1235 peptide-expressing malignancies.

Original languageEnglish
Pages (from-to)5201-5210
Number of pages10
JournalAnticancer Research
Volume32
Issue number12
Publication statusPublished - 01-12-2012

Fingerprint

Peptide T
T-Cell Antigen Receptor
Epitopes
Peptides
Leukemia
T-Cell Receptor Genes
Cytotoxic T-Lymphocytes
Neoplasms
Vaccination
Wilms' Tumor Genes
T-Lymphocytes
Neoplasm Antigens
Amino Acid Substitution
Immunotherapy
Interferons
Clone Cells
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Taichi, T., Oka, Y., Fujiki, F., Tsuboi, A., Katsuhara, A., Nakajima, H., ... Sugiyama, H. (2012). Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. Anticancer Research, 32(12), 5201-5210.
Taichi, Tamanaka ; Oka, Yoshihiro ; Fujiki, Fumihiro ; Tsuboi, Akihiro ; Katsuhara, Akiko ; Nakajima, Hiroko ; Hosen, Naoki ; Nishida, Sumiyuki ; Lin, Yu Hung ; Tachino, Sho ; Akatsuka, Yoshiki ; Kuzushima, Kiyotaka ; Oji, Yusuke ; Kumanogoh, Atsushi ; Sugiyama, Haruo. / Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. In: Anticancer Research. 2012 ; Vol. 32, No. 12. pp. 5201-5210.
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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 WT1235peptide, which has one amino acid substitution (M→Y) at position 2 of 9-mer natural WT1235 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 WT1235 peptide-recognizing cytotoxic T-lymphocytes (CTLs) and exerted cytotoxic activity towards leukemia and solid tumor cells that expressed the natural WT1235 peptide (epitope) but not the vaccinated modified WT1235 peptide (epitope), the molecular basis has remained unclear. In this study, we established a modified WT1235 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 WT1235 peptide but also with the natural WT1235 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 WT1235 peptide-based immunotherapy for natural WT1235 peptide-expressing malignancies.",
author = "Tamanaka Taichi and Yoshihiro Oka and Fumihiro Fujiki and Akihiro Tsuboi and Akiko Katsuhara and Hiroko Nakajima and Naoki Hosen and Sumiyuki Nishida and Lin, {Yu Hung} and Sho Tachino and Yoshiki Akatsuka and Kiyotaka Kuzushima and Yusuke Oji and Atsushi Kumanogoh and Haruo Sugiyama",
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Taichi, T, Oka, Y, Fujiki, F, Tsuboi, A, Katsuhara, A, Nakajima, H, Hosen, N, Nishida, S, Lin, YH, Tachino, S, Akatsuka, Y, Kuzushima, K, Oji, Y, Kumanogoh, A & Sugiyama, H 2012, 'Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor', Anticancer Research, vol. 32, no. 12, pp. 5201-5210.

Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. / Taichi, Tamanaka; Oka, Yoshihiro; Fujiki, Fumihiro; Tsuboi, Akihiro; Katsuhara, Akiko; Nakajima, Hiroko; Hosen, Naoki; Nishida, Sumiyuki; Lin, Yu Hung; Tachino, Sho; Akatsuka, Yoshiki; Kuzushima, Kiyotaka; Oji, Yusuke; Kumanogoh, Atsushi; Sugiyama, Haruo.

In: Anticancer Research, Vol. 32, No. 12, 01.12.2012, p. 5201-5210.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor

AU - Taichi, Tamanaka

AU - Oka, Yoshihiro

AU - Fujiki, Fumihiro

AU - Tsuboi, Akihiro

AU - Katsuhara, Akiko

AU - Nakajima, Hiroko

AU - Hosen, Naoki

AU - Nishida, Sumiyuki

AU - Lin, Yu Hung

AU - Tachino, Sho

AU - Akatsuka, Yoshiki

AU - Kuzushima, Kiyotaka

AU - Oji, Yusuke

AU - Kumanogoh, Atsushi

AU - Sugiyama, Haruo

PY - 2012/12/1

Y1 - 2012/12/1

N2 - 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 WT1235peptide, which has one amino acid substitution (M→Y) at position 2 of 9-mer natural WT1235 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 WT1235 peptide-recognizing cytotoxic T-lymphocytes (CTLs) and exerted cytotoxic activity towards leukemia and solid tumor cells that expressed the natural WT1235 peptide (epitope) but not the vaccinated modified WT1235 peptide (epitope), the molecular basis has remained unclear. In this study, we established a modified WT1235 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 WT1235 peptide but also with the natural WT1235 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 WT1235 peptide-based immunotherapy for natural WT1235 peptide-expressing malignancies.

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Taichi T, Oka Y, Fujiki F, Tsuboi A, Katsuhara A, Nakajima H et al. Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. Anticancer Research. 2012 Dec 1;32(12):5201-5210.