Invariant NKT cell-based effector T cell expressing a tumor reactive T cell receptor, as a possible cell medicine for pancreatic cancer

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592022
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: UEMURA Yasushi 愛知県がんセンター(研究所), 腫瘍免疫学部, 主任研究員 (40364781)
• Co-Investigator(Renkei-kenkyūsha): KUZUSHIMA Kiyotaka 愛知県がんセンター研究所, 部長 (30311442) ; SENJU Satoru 熊本大学, 医学薬学研究部, 准教授 (50274709) ; OKAMURA Ayako 愛知県がんセンター研究所, 研究員 (10546948)
• Project Period (FY): 2011 – 2013
• Keywords: 外科 / 膵臓癌 / 免疫

Research Abstract

Currently, cancer antigen-derived T cell epitope peptide vaccines are under development and clinical trials have already been performed. Unfortunately, outcomes have been disappointing. To address these issues, we focused on invariant NKT cells that recognize alpha-GalCer presented by CD1d. We established iNKT cell-based anti-tumor effector T cells that express a tumor reactive T cell receptor (TCR). The TCR-transduced CD4-CD8- (DN) iNKT cells were excellent for tumor antigen-specific cytotoxicity. In contrast, the TCR-transduced CD4+CD8- (CD4) iNKT cells acted as a cellular adjuvant inducing robust IL-12p70 production in alpha-GalCer-loaded dendritic cells. Tumor-reactive TCR-expressing iNKT cell that exert cytotoxic activity and adjuvant activity may be a powerful tool for cancer immunotherapy.

Research Products

• [Journal Article] Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation (2013)
  • Author(s): Nishimura T, Kaneko S, Kawana-Tachikawa A, Tajima Y, Gotoh H, Zhu D, Nakayama K, Iriguchi S, Uemura Y, Shimizu T, Takayama N, Yamada D, Nishimura K, Ohtaka M, Watanabe N, Takahashi S, Iwamoto A, Koseki H, Nakanishi M, Eto K, Nakauchi H.
  • Journal Title: Cell Stem Cell Volume: 12 Pages: 114-126
  • DOI: 10.1016/j.stem.2012.11.002
• [Journal Article] An HLA-modified ovarian cancer cell line induced CTL responses specific to an epitope derived from claudin-1 presented by HLA-A*24:02 molecules (2013)
  • Author(s): Kondo S, Demachi-Okamura A, Hirosawa T, Maki H, Fujita M, Uemura Y, Akatsuka Y, Yamamoto E, Shibata K, Ino K, Kikkawa F, Kuzushima K.
  • Journal Title: Hum Immunol Volume: 74 Pages: 1103-1110
  • DOI: 10.1016/j.humimm.2013.06.030
• [Journal Article] Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by humanγδT cells (2012)
  • Author(s): Nishio N., Fujita M., Tanaka Y., Maki H., Zhang R, Hirosawa T., Demachi-Okamura A., Uemura Y., Taguchi O., Takahashi Y., Kojima S., Kuzushima K.
  • Journal Title: J . Immunother. Volume: 35 Pages: 598-606
• [Journal Article] CXCL8 enhances the angiogenic activity of umbilical cord blood-derived outgrowth endothelial cells in vitro (2011)
  • Author(s): Kimura, T., Kohno, H., Matsuoka, Y., Murakami, M., Nakatsuka, R., Hase, M., Yasuda, K., Uemura, Y., Sasaki, Y., Fukunaga, S., and Sonoda, Y.
  • Journal Title: Cell Biol Int. Volume: 35 Pages: 201-208
  • DOI: 10.1042/CBI20090225
• [Journal Article] The low level of c-kit expression marks deeply quiescent murine hematopoietic stem cells (2011)
  • Author(s): Matsuoka Y., Sasaki Y., Nakatsuka R., Takahashi M., Iwaki R., Uemura Y., and Sonoda Y.
  • Journal Title: Stem Cells Volume: 29 Pages: 1783-1791
  • DOI: 10.1002/stem.721
• [Presentation] Pluripotent stem cell-derived myeloid cells expressing TRAIL as a possible cell medicine for cancer (2013)
  • Author(s): Hiroyuki Maki, Yasushi Uemura, Rong Zhang, Tianyi Liu, Motoharu Suzuki, Narumi Hirosawa, Kazuyoshi Takeda, Yasushi Sakamoto, Satoru Senju, Kiyotaka Kuzushima
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉市
  • Year and Date: 20131211-13
• [Presentation] 多能性幹細胞由来の増殖性ミエロイド細胞を用いたがん免疫療法の開発 (2013)
  • Author(s): 張エイ, 劉天懿, 千住覚, 廣澤成美, 辻村邦夫, 中西速夫, 薗田精昭, 坂本安, 西村泰治, 葛島清隆, 植村靖史
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 20131003-05
• [Presentation] TRAILを発現する多能性幹細胞由来ミエロイド細胞を用いた細胞医薬の開発 (2013)
  • Author(s): 牧寛之, 植村靖史, 張エイ, 竹田和由, 劉天懿, 鈴木元晴, 都築忍, 岡村文子, 赤塚美樹, 西村泰治, 千住覚, 葛島清隆
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 20131003-05
• [Presentation] Investigation on toxic effects of organophosphate pesticide to endocrine organs related to reproductive system, and identification of target molecules of the chemicals in these organs (2012)
  • Author(s): Narumi Hirosawa, Takeshi Sakamoto, Yasushi Uemura, Yuko Suzuki, Yasushi Sakamoto
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡市
  • Year and Date: 20121214-16
• [Presentation] Regulation of IL-27/Osteopontin balance in dendritic cells by ligand activation of invariant NKT cells (2012)
  • Author(s): Rong Zhang, Tianyi Liu, Motoharu Suzuki, Narumi Hirosawa, Shin Kaneko, Ayako Okamura, Yasushi Sakamoto, Kiyotaka Kuzushima, and Yasushi Uemura
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
  • Year and Date: 20121205-07
• [Presentation] 23価肺炎球菌ワクチン接種後の抗体産生におけるNKT細胞の役割に関する臨床免疫学的検討 (2012)
  • Author(s): 宮坂智充, 青柳哲史, 内山美寧, 國島広之, 賀来満夫, 中山俊憲, 植村靖史, 大石和徳, 金城雄樹, 宮崎義継, 川上和義
  • Organizer: 第16回日本ワクチン学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 20121117-18
• [Presentation] Tumor-reactive TCR gene-transduced invariant NKT cells as a possible tool for cancer immunotherapy (2012)
  • Author(s): Yasushi Uemura, Junichi Mineno, Hiroaki Ikeda, Tianyi Liu, Hiroyuki Maki, Shinji Kondo, Rong Zhang, Ayako Okamura, Mitsugu Fujita, Yoshiki Akatsuka, Yoshiaki Sonoda, Hiroshi Shiku, and Kiyotaka Kuzushima
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] Modification of IL-12p70/Osteopontin balance in dendritic cells by ligand activation of invariant NKT cells (2012)
  • Author(s): Motoharu Suzuki, Tianyi Liu, Narumi Hirosawa, Yayoi Nobori, Ayako Okamura, Yasushi Sakamoto, Kiyotaka Kuzushima, and Yasushi Uemura
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] FACSにより予期的に分離されたマウスSca-1, PDGFRα陽性歯髄幹細胞は同一の表面免疫特性を持つ骨髄由来間葉系幹細胞とは異なる幹細胞特性を有する (2012)
  • Author(s): 中塚隆介, 植村靖史, 薗田精昭
  • Organizer: 第54回歯科基礎医学会学術大会・総会
  • Place of Presentation: 奥羽大学記念講堂
  • Year and Date: 20120914-16
• [Presentation] ヒト造血幹細胞支持能を有するヒト骨髄由来間葉系幹細胞の予期的分離 (2012)
  • Author(s): 松岡由和, 高橋雅也, 岩城隆二, 佐々木豊, 中塚隆介, 河野比良夫, 植村靖史, 井上雅美, 小川啓恭, 高橋隆幸, 石川淳, 日野雅之, 薗田精昭
  • Organizer: 第34回日本造血細胞移植学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 20120224-25
• [Presentation] ヒトインバリアントNKT細胞を用いたがん免疫療法の可能性(教育講演) (2012)
  • Author(s): 植村靖史
  • Organizer: 第34回日本造血細胞移植学会総会
  • Place of Presentation: 大阪
  • Year and Date: 20120224-25
• [Presentation] Zoledronate sensitizes neuroblastoma-derived tumor-initiating cells to cytolysis mediated by human gamma-delta T cells (2012)
  • Author(s): 西尾信博, 藤田貢, 田中義正, 牧寛之, 張エイ, 岡村文子, 植村靖史, 田口修, 高橋義行, 小島勢二, 葛島清隆
  • Organizer: 第4回造血器腫瘍免疫療法研究会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 20120000
• [Presentation] 内因性HLAの発現を抑制し目的のHLA-A24を発現する人工抗原提示細胞を用いた卵巣がんを傷害するCTLの誘導 (2011)
  • Author(s): 近藤紳司, 岡村文子, 牧寛之, Zhang Rong ,植村靖史, 藤田貢, 山本英子, 柴田清住, 吉川史隆, 葛島清隆
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 20111003-1005
• [Presentation] 内因性HLAの発現を抑制し目的のHLA-A24を発現する人工抗原提示細胞を用いた卵巣癌を傷害するCTLの誘導 (2011)
  • Author(s): 近藤紳司, 岡村文子, 牧寛之, Zhang Rong, 植村靖史, 藤田貢, 山本英子, 柴田清住, 吉川史隆, 葛島清隆
  • Organizer: 第15回日本がん免疫学会総会
  • Place of Presentation: 大阪府豊中市
  • Year and Date: 20110630-0701
• [Remarks]
  • URL: http://www.pref.aichi.jp/cancer-center/ri/index.html