WT1特異的細胞傷害性T細胞の長期的活性維持に関与する遺伝子の同定

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25830116
• Research Institution: Osaka University
• Principal Investigator: 森本 創世子 大阪大学, 医学(系)研究科(研究院), 研究員 (10649023)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: WT1特異的CTL

Outline of Annual Research Achievements

これまでの研究結果より、WT1特異的エフェクターメモリーCTLの増加またはその存在頻度がWT1ペプチドワクチン投与前後で維持されることが良好な臨床効果をもたらすと考えていた。しかし、WT1特異的エフェクターメモリーCTLが増加してもWT1ペプチドワクチンが効かない症例や、WT1特異的エフェクターメモリーCTLの存在頻度が少ないにもかかわらずWT1ペプチドワクチンが効き、良好な臨床効果をもたらした症例などがあった。WT1ペプチドワクチン療法の臨床試験を通したこのような知見より我々は、エフェクターメモリーといっても特定の細胞表面マーカーによって分類されただけで、一つ一つの細胞は遺伝子背景やそれに基づく機能の異なるheterogeneousな細胞集団であり、この細胞集団の中に長期的に腫瘍細胞傷害活性を維持する機能をもつCTLが存在し、それらはエフェクターメモリーよりも未分化な遺伝子背景を持つと考えた。そこで、stem性やmemoryに関与すると予想される83種類の遺伝子セットを選択し、癌患者末梢血中単核球(PBMC)中のWT1特異的エフェクターメモリーCTLについてこれら83種類の遺伝子発現強度を解析した。
実際、WT1ペプチドワクチン投与前の9名の癌患者PBMCからWT1特異的エフェクターメモリーCTLを307個得て、個々の細胞に対してそれぞれ83種類の遺伝子発現強度を調べたところ、遺伝子発現強度によってWT1特異的エフェクターメモリーCTLがGroup AとBの2群に分かれることが明らかになった。さらに、83種類の遺伝子発現を指標に主成分分析を行ったところ、これら2群は主成分1(PC1)によって分かれ、83種類の遺伝子のうちPC1を強く説明する遺伝子が明らかとなった。

Research Products

• [Journal Article] Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients (2015)
  • Author(s): Yoshiki Nakae, Yoshihiro Oka, Fumihiro Fujiki, Soyoko Morimoto, Toshio Kamiya, Satoshi Takashima, Jun Nakata, Sumiyuki Nishida, Hiroko Nakajima, Naoki Hosen, Akihiro Tsuboi, Taiichi Kyo, Yusuke Oji, Kenji Mizuguchi, Atsushi Kumanogoh, Haruo Sugiyama
  • Journal Title: Cancer Immunology Immunotherapy Volume: - Pages: -
  • DOI: 10.1007/s00262-015-1683-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transduction of a novel HLA-DRB1*04:05-restricted, WT1-specific TCR gene into human CD4+T cells confers killing activity against human leukemia cells (2015)
  • Author(s): Akiko Katsuhara, Fumihiro Fujiki, Nao Aoyama, Satoe Tanii, Soyoko Morimoto, Yoshihiro Oka, Akihiro Tsuboi, Hiroko Nakajima, Kenta Kondo, Naoya Tatsumi, Jun Nakata, Yoshiki Nakae, Satoshi Takashima, Sumiyuki Nishida, Naoki Hosen, Shinji Sogo, Yusuke Oji, Haruo Sugiyama
  • Journal Title: Anticancer Research Volume: 35 Pages: 1251-1262
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response (2015)
  • Author(s): Naoya Hashimoto, Akihiro Tsuboi, Naoki Kagawa, Yasuyoshi Chiba, Shuichi Izumoto, Manabu Kinoshita, Noriyuki Kijima, Yoshihiro Oka, Soyoko Morimoto, Hiroko Nakajima, Satoshi Morita, Junichi Sakamoto, Sumiyuki Nishida, Naoki Hosen, Yusuke Oji, Norio Arita, Toshiki Yoshimine, Haruo Sugiyama
  • Journal Title: Cancer Immunology Immunotherapy Volume: - Pages: -
  • DOI: 10.1007/s00262-015-1674-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Analysis of correlation of WT1-specific immune responses before WT1 peptide vaccination and clinical responses (2014)
  • Author(s): Soyoko Morimoto, Yoshihiro Oka, Akihiro Tsuboi, Naoki Hosen, Sumiyuki Nishida, Fumihiro Fujiki, Hiroko Nakajima, Yusuke Oji, Haruo Sugiyama
  • Organizer: The 7th International Conference on WT1 in human neoplasia
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-04-22 – 2014-04-23
• [Presentation] Gemcitabine plus WT1 peptide-based cancer vaccine versus gemcitabine alone for advanced pancreatic cancer: a randomized phase II clinical study in multi-centre-interim analysis (2014)
  • Author(s): Sumiyuki Nishida, Shinichi Egawa, Satoshi Kokura, Takeshi Ishikawa, Shigeo Koido, Sadamu Homma, Soyoko Morimoto, Satoshi Morita, Yoshihiro Oka, Haruo Sugiyama
  • Organizer: The 7th International Conference on WT1 in human neoplasia
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-04-22 – 2014-04-23
• [Presentation] Response assessments in WT1 peptide vaccination an long term results of combined temozolomide therapy (2014)
  • Author(s): Naoya Hashimoto, Akihiro Tsuboi, Yasuyoshi Chiba, Yoshihiro Oka, Soyoko Morimoto, Hiroko Nakajima, Sumiyuki Nishida, Naoki Hosen, Naoki Kagawa, Yusuke Oji, Toshiki Yoshimine, Haruo Sugiyama
  • Organizer: The 7th International Conference on WT1 in human neoplasia
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-04-22 – 2014-04-23
• [Presentation] Wilms' tumor gene 1 (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer (2014)
  • Author(s): Shigeo Koido, Sumiyuki Nishida, Sadamu Homma, Yutaka Takeda, Hideo Komita, Satoshi Morita, Toshinori Ito, Soyoko Morimoto, Yoshihiro Oka, Satoru Yanagisawa, Yoichi Toyama, Masahiro Ikegami, Hiroaki Nagano, Toshifumi Ohkusa, Hisao Tajiri, Haruo Sugiyama
  • Organizer: AACR Annual Meeting
  • Place of Presentation: San Diego, CA
  • Year and Date: 2014-04-05 – 2014-04-09