Reprogramming and re-differentiation of invariant NKT cells for pancreatic cancer immunotherapy

• Project/Area Number: 26462078
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: National Cancer Center Japan
• Principal Investigator: UEMURA Yasushi 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (40364781)
• Co-Investigator(Kenkyū-buntansha): 張 エイ 国立研究開発法人国立がん研究センター, 先端医療開発センター, 研究員 (00643719)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 外科 / 膵臓 / がん / 免疫 / 再生免疫学 / 免疫療法 / 細胞療法

Outline of Final Research Achievements

Vα24 invariant natural killer T (iNKT) cells are a subset of T lymphocytes implicated in the regulation of broad immune responses. Reduced iNKT cell numbers and function have been observed in many patients with cancer. To recover these numbers, we reprogrammed human iNKT cells to pluripotency and then re-differentiated them into regenerated iNKT cells in vitro through an IL-2/IL-15-based optimized cytokine combination. The re-differentiated iNKT cells showed proliferation and IFN-γ production in response to α-galactosylceramide, induced dendritic cell maturation and downstream activation of cytotoxic T lymphocytes, and exhibited NKG2D- and DNAM-1-mediated NK cell-like cytotoxicity against cancer cell lines.
The immunological features of re-differentiated iNKT cells and their unlimited availability from induced pluripotent stem cells offer a potentially effective immunotherapy against pancreatic cancer.

Research Products

• [Journal Article] Enhancement of antitumor effect by peptide vaccine therapy in combination with anti-CD4 antibody: Study in a murine mode. (2016)
  • Author(s): Fujinami N, Yoshikawa T, Sawada Y, Shimomura M, Iwama T, Sugai S, Kitano S, Uemura Y, Nakatsura N.
  • Journal Title: Biochemistry and Biophysics Reports Volume: 5 Pages: 482-491
  • Peer Reviewed / Open Access
• [Journal Article] BCR-ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells (2016)
  • Author(s): Ueda N, Zhang R, Tatsumi M, Liu TY, Kitayama S, Yasui Y, Sugai S, Iwama T, Senju S, Okada S, Nakatsura T, Kuzushima K, Kiyoi H, Naoe T, Kaneko S, Uemura Y.
  • Journal Title: Cell Mol Immunol. Volume: - Issue: 1 Pages: 15-26
  • DOI: 10.1038/cmi.2016.7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cellular Adjuvant Properties, Direct Cytotoxicity of Re-differentiated Va24 Invariant NK T-like Cells from Human Induced Pluripotent Stem Cells (2016)
  • Author(s): Kitayama S, Zhang R, Liu TY, Ueda N, Iriguchi S, Yasui Y, Kawai Y, Tatsumi M, Hirai N, Mizoro Y, Iwama T, Watanabe A, Nakanishi M, Kuzushima K, Uemura Y, Kaneko S
  • Journal Title: Stem Cell Reports Volume: 6 Issue: 2 Pages: 213-227
  • DOI: 10.1016/j.stemcr.2016.01.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatocellular carcinoma cell sensitivity to Vg9Vd2 T lymphocyte-mediated killing is increased by zoledronate. (2016)
  • Author(s): Sugai S, Yoshikawa T, Iwama T, Tsuchiya N, Ueda N, Fujinami N, Shimomura M, Zhang R, Kaneko S, Uemura Y, Nakatsura T.
  • Journal Title: Int J Oncol. Volume: 48 (5) Issue: 5 Pages: 1794-1804
  • DOI: 10.3892/ijo.2016.3403
  • Peer Reviewed / Open Access
• [Journal Article] Vaccination with liposome-coupled glypican-3-derived epitope peptide stimulates cytotoxic T lymphocytes and inhibits GPC3-expressing tumor growth in mice. (2016)
  • Author(s): Iwama T, Uchida T, Sawada Y, Tsuchiya N, Sugai S, Fujinami N, Shimomura M, Yoshikawa T, Zhang R, Uemura Y, Nakatsura T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 469(1) Issue: 1 Pages: 138-43
  • DOI: 10.1016/j.bbrc.2015.11.084
  • Peer Reviewed / Open Access
• [Journal Article] Identification and Characterization of Lineage(-)CD45(-)Sca-1(+) VSEL Phenotypic Cells Residing in Adult Mouse Bone Tissue. (2016)
  • Author(s): Nakatsuka R, Iwaki R, Matsuoka Y, Sumide K, Kawamura H, Fujioka T, Sasaki Y, Uemura Y, Asano H, Kwon AH, Sonoda Y.
  • Journal Title: Stem Cells Dev. Volume: 25 (1) Issue: 1 Pages: 27-42
  • DOI: 10.1089/scd.2015.0168
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Generation of mouse pluripotent stem cell-derived proliferating myeloid cells as an unlimited source of functional antigen-presenting cells (2015)
  • Author(s): Zhang R, Liu T, Senju S, Haruta M, Hirosawa N, Suzuki M, Tatsumi M, Ueda N, Maki H, Nakatsuka R, Matsuoka Y, Sasaki Y, Tsuzuki S, Nakanishi H, Araki R, Abe M, Akatsuka Y, Sakamoto Y, Sonoda Y, Nishimura Y, Kuzushima K, Uemura Y
  • Journal Title: Cancer Immunol Res Volume: 印刷中 Issue: 6 Pages: 668-677
  • DOI: 10.1158/2326-6066.cir-14-0117
  • Peer Reviewed
• [Journal Article] Generation of mouse pluripotent stem cell-derived proliferating myeloid cells as an unlimited source of functional antigen-presenting cells. (2015)
  • Author(s): Zhang R., Liu T., Senju S., Haruta M., Hirosawa N., Suzuki M., Tatsumi M., Ueda N., Maki H., Nakatsuka R, Matsuoka Y., Sasaki Y., Tsuzuki S., Nakanishi H., Araki R., Abe M., Akatsuka Y., Sakamoto Y., Sonoda Y., Nishimura Y., Kuzushima K. and Uemura Y.
  • Journal Title: Cancer Immunol. Res. Volume: Feb11
  • Peer Reviewed
• [Journal Article] Prospectively isolated human bone marrow cell-derived MSCs support primitive human CD34-negative hematopoietic stem cells (2015)
  • Author(s): Matsuoka Y, Nakatsuka R, Sumide K, Kawamura H, Takahashi M, Fujioka T, Uemura Y, Asano H, Sasaki Y, Inoue M, Ogawa H, Takahashi T, Hino M, Sonoda Y
  • Journal Title: Stem Cells Volume: 33 Issue: 5 Pages: 1554-1565
  • DOI: 10.1002/stem.1941
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] iNKT細胞と樹状細胞の相互作用によるIL-27/osteopontin産生制御 (2014)
  • Author(s): 張エイ, 劉天懿, 鈴木元晴, 廣澤成美, 坂本安, 葛島清隆, 植村靖史
  • Journal Title: 臨床免疫・アレルギー科 Volume: 61 Pages: 158-163
• [Journal Article] iNKT細胞による樹状細胞の機能修飾 (2014)
  • Author(s): 張エイ, 鈴木元晴, 上田格弘, 巽美奈子, 劉天懿, 葛島清隆, 植村靖史
  • Journal Title: 臨床免疫・アレルギー科 Volume: 62 Pages: 303-313
  • NAID: 40020210773
• [Presentation] Cellular adjuvant properties and direct cytotoxicity in rejuvenated Vα24 invariant NKT cells from human induced pluripotent stem cells (2016)
  • Author(s): ZHANG Rong, KITAYAMA Syuichi, LIU Tianyi, UEDA Norihiro, IWAMA Tatsuaki, NAKATSURA Tetsuya, KUZUSHIMA Kiyotaka, KANEKO Shin, UEMURA Yasushi
  • Organizer: 第45回日本免疫学会学術総会
  • Place of Presentation: 沖縄コンベンションセンター・宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] Therapeutic potential of dasatinib for acute graft versus leukemia disease (2016)
  • Author(s): 張 エイ, 上田 格弘, 喜多山 秀一, 安井 裕, 土屋 伸広, 劉 天懿, 岩間 達章, 葛島 清隆, 中面 哲也, 清井 仁 , 金子 新, 植村 靖史
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜・横浜市
  • Year and Date: 2016-10-06
• [Presentation] CD4-modification of re-differentiated BCR-ABL-specific T cells promote the priming of leukemia antigen-specific CTLs via DCs (2016)
  • Author(s): 上田格弘, 植村 靖史, 張 エイ, 喜多山 秀一, 安井 裕, 巽 美奈子, 劉 天懿, 葛島 清隆, 清井 仁 , 金子 新
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜・横浜市
  • Year and Date: 2016-10-06
• [Presentation] iPSC-pMCs genetically engineered to express IFNα as a potential cell medicine for cancer (2016)
  • Author(s): TSUCHIYA Nobuhiro, UEMURA Yasushi, IWAMA Tatsuaki, ZHANG Rong, SUZUKI Toshihiro, YOSHIKAWA Toshiaki, SAWADA Yu, TAKUBO Keiyo, SAKAGAMI-SAWANO Asako, MIYAWAKI Atsushi, ENDO Itaru, NAKATSURA Tetsuya
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜・横浜市
  • Year and Date: 2016-10-06
• [Presentation] インターフェロンαを産生するiPS細胞由来増殖性ミエロイド細胞を用いたがん免疫療法 (2016)
  • Author(s): 土屋 伸広, 植村 靖史, 岩間 達章, 張 エイ, 得光 友美, 鈴木 利宙, 吉川 聡明, 澤田 雄, 田久保 圭誉, 阪上-沢野 朝子, 宮脇 敦史, 遠藤 格, 中面 哲也
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大阪カンファレンスセンター＆ホテル・大阪市
  • Year and Date: 2016-07-27
• [Presentation] Generation of BCR-ABL Reactive CD4+ T Helper Cells By Reprograming and Redifferentiation (2015)
  • Author(s): Norihiro Ueda, Yasushi Uemura, Zhang Rong, Shuichi Kitayama, Yutaka Yasui, Minako Tatsumi, Tian-Yi Liu, Kiyotaka Kuzushima, Hitoshi Kiyoi,Tomoki Naoe, Shin Kaneko
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Interaction of Va24 iNKT cells with dendritic cells increases the therapeutic efficacy of TCR-gene modified T cells (2015)
  • Author(s): Rong Zhang, Yasushi Uemura, Tianyi Liu, Sachiko Okamoto, Hiroaki Ikeda, Minako Tatsumi, Mitsuhiro Takenoyama, Yoshiki Akatsuka, Seiji Okada, Junichi Mineno, Hiroshi Shiku, Kiyotaka Kuzushima
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場・名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Generation of BCR-ABL reactive CD4 T lymphocytes by reprograming and redifferentiation (2015)
  • Author(s): Norihiro Ueda, Yasushi Uemura, Rong Zhang, Shuichi Kitayama, Yutaka Yasui, Minako Tatsumi, Tian-Yi Liu, Shiori Sugai, Kiyotaka Kuzushima, Hitoshi Kiyoi, Shin Kaneko
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場・名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Regulation of IL-12 family cytokine/Osteopontin balance in DCs by ligand activation of iNKT cells. (2015)
  • Author(s): Tatsuaki Iwama, Motoharu Suzuki, Tianyi Liu, Rong Zhang, Toshiaki Yoshikawa, Manami Shimomura, Tetsuya Nakatsura, Kiyotaka Kuzushima and Yasushi Uemura.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場・名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Vaccination of GPC3-derived peptide-coupled liposome inhibits GPC3 expressing tumor growth. (2015)
  • Author(s): TSUCHIYA Nobuhiro, IWAMA Tatsuaki, UCHIDA Tetsuya, SHIMOMURA Manami, YOSHIKAWA Toshiaki, FUJINAMI Norihiro, SAITO Yuki, UEMURA Yasushi, NAKATSURA Tetsuya.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場・名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Generation of BCR-ABL reactive CD4 T lymphocytes by reprograming and redifferentiation (2014)
  • Author(s): Norihiro Ueda, Yasushi Uemura, Rong Zhang, Tian-Yi Liu, Minako Tatsumi, Yutaka Yasui, Kiyotaka Kuzushima, Hitoshi Kiyoi, Shin Kaneko
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館 京都市
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] BCR-ABL–specific T helper cells facilitate propagation of antigen-specific CTLs via DC maturation. (2014)
  • Author(s): 上田格弘, 植村靖史, 張エイ, 劉天懿, 巽美奈子, 安井裕, 葛島清隆, 清井仁, 金子新
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪市
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Generation of BCR-ABL reactive CD4 T lymphocytes by reprograming and redifferentiation. (2014)
  • Author(s): 上田格弘, 植村靖史, 張エイ, 劉天懿, 巽美奈子, 安井裕, 葛島清隆, 清井仁, 金子新
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Analysis of glypican-3 specific CTLs in the tumor tissue and vaccination site after administration of GPC3 peptide (2014)
  • Author(s): 吉川聡明, 下村真菜美, 澤田雄, 植村靖史, 中面哲也
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Establishment of three-dimensional primary tumor cell culture method and novel drug sensitivity test (2014)
  • Author(s): 下村真菜美, 五字弘, 伊藤学, 植村靖史, 中面哲也
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] The enhancement of the CTL induction by peptide vaccine therapy in combination with anti-CD4 antibody (2014)
  • Author(s): Fujinami Norihiro, Yoshikawa Toshiaki, Sawada Yu, Shimomura Manami, Iwama Tatsuaki, Uemura Yasushi, Nakatsura Tetsuya
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Glypican-3 (GPC3)ペプチドワクチン投与後の投与局所及び腫瘍局所でのペプチド特異的CTLの解析 (2014)
  • Author(s): 吉川聡明, 下村真菜美, 澤田雄, 高橋真理, 吉原宏樹, 上野浩生, 真部淳, 細野亜古, 植村靖史, 中面哲也
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール 松山市
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] BCR-ABL特異的ヘルパーT細胞のリプログラミングとCML治療への応用 (2014)
  • Author(s): 上田格弘, 植村靖史, 張エイ, 劉天懿, 巽美奈子, 安井裕, 葛島清隆, 清井仁, 金子新
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめぎんホール 松山市
  • Year and Date: 2014-07-30 – 2014-08-01
• [Patent(Industrial Property Rights)] CD4陽性細胞の製造方法 (2015)
  • Inventor(s): 金子 新, 上田 格弘, 植村 靖史
  • Industrial Property Rights Holder: 金子 新, 上田 格弘, 植村 靖史
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-11-13