Type I IFN-producing myeloid cells as a cell preparation for lung caner

• Project/Area Number: 17K10806
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: National Cancer Center Japan
• Principal Investigator: Fukuda Kyoko 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)
• Co-Investigator(Kenkyū-buntansha): 千住 覚 熊本大学, 大学院生命科学研究部(医), 准教授 (50274709)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 外科 / がん / 免疫 / インターフェロン / 人工多能性幹細胞 / がん免疫療法 / 免疫療法 / ミエロイド細胞 / 1型インターフェロン

Outline of Final Research Achievements

Type I interferons (IFNs) play important roles in antitumor immunity. We generated
IFN-α-producing cells by genetically engineering induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1+ dendritic cells to enhance CD8+ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.

Academic Significance and Societal Importance of the Research Achievements

IFN-α-pMCの抗腫瘍効果の詳細なメカニズムを明らかにしたところに学術的意義を有する。特にIFN-α-pMCによって産生される1型IFNの作用点を決定した点は注目に値する。また、免疫チェックポイント阻害剤抵抗性のがんを克服するための新たな医療技術が提案され社会的意義は大きい。

Research Products

• [Journal Article] In Vitro Detection of Cellular Adjuvant Properties of Human Invariant Natural Killer T Cells (2019)
  • Author(s): Zhang Rong、Kitayama Shuichi、Liu Tianyi、Ueda Norihiro、Tokumitsu Yumi、Mashima Hiroaki、Ohdan Hideki、Kaneko Shin、Uemura Yasushi
  • Journal Title: Methods Mol Biol Volume: 2048 Pages: 121-130
  • DOI: 10.1007/978-1-4939-9728-2_13
  • ISBN: 9781493997275, 9781493997282
  • Peer Reviewed / Open Access
• [Journal Article] Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells. (2019)
  • Author(s): Tsuchiya N, Zhang R, Iwama T, Ueda N, Liu T, Tatsumi M, Sasaki Y, Shimoda R, Osako Y, Sawada Y, Kubo Y, Miyashita A, Fukushima S, Cheng Z, Nakaki R, Takubo K, Okada S, Kaneko S, Ihn H, Kaisho T, Nishimura Y, Senju S, Endo I, Nakatsura T, Uemura Y.
  • Journal Title: Cell Rep. Volume: 29 Issue: 1 Pages: 162-175
  • DOI: 10.1016/j.celrep.2019.08.086
  • Peer Reviewed / Open Access
• [Journal Article] Enhancing T cell Receptor Stability in Rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy (2018)
  • Author(s): Minagawa A, Yoshikawa T, Yasukawa M, Hotta A, Kunitomo M, Iriguchi S, Takiguchi M, Kassai Y, Imai E, Yasui Y, Kawai Y, Zhang R, Uemura Y, Miyoshi H, Nakanishi M, Watanabe A, Hayashi A, Kawana K, Fujii T, Nakatsura T, Kaneko S
  • Journal Title: Cell Stem Cell Volume: 23 Issue: 6 Pages: 850-858
  • DOI: 10.1016/j.stem.2018.10.005
  • Peer Reviewed / Open Access
• [Journal Article] Generation of TCR-Expressing Innate Lymphoid-like Helper Cells that Induce Cytotoxic T Cell-Mediated Anti-leukemic Cell Response. (2018)
  • Author(s): Ueda N, Uemura Y, Zhang R, Kitayama S, Iriguchi S, Kawai Y, Yasui Y, Tatsumi M, Ueda T, Liu TY, Mizoro Y, Okada C, Watanabe A, Nakanishi M, Senju S, Nishimura Y, Kuzushima K, Kiyoi H, Naoe T, Kaneko S
  • Journal Title: Stem Cell Reports Volume: 10 Issue: 6 Pages: 1935-1946
  • DOI: 10.1016/j.stemcr.2018.04.025
  • NAID: 120006473765
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Co-delivery of tumor-derived exosomes with alpha-galactosylceramide on dendritic cell-based immunotherapy for glioblastoma (2017)
  • Author(s): Liu H, Chen L, Liu J, Meng H, Zhang R, Ma L, Wu L, Yu S, Shi F, Li Y, Zhang L, Wang L, Feng S, Zhang Q, Peng Y, Wu Q, Liu C, Chang X, Yang L, Uemura Y, Yu X, Liu T.
  • Journal Title: Cancer Lett. Volume: 411 Pages: 182-190
  • DOI: 10.1016/j.canlet.2017.09.022
  • Peer Reviewed / Int'l Joint Research
• [Presentation] iPSCに由来するプロフェッショナル抗原提示細胞を用いた新規がんワクチン療法の開発 (2019)
  • Author(s): 真島宏聡, 張エイ, 小林剛 岩間達章, 大段秀樹, 中面哲也, 植村靖史
  • Organizer: 第40回癌免疫外科研究会
• [Presentation] 人工多能性幹細胞に由来するプロフェッショナル抗原提示細胞を用いた新規がんワクチン療法の開発 (2019)
  • Author(s): 真島宏聡, 張エイ, 小林剛, 岩間達章, 大段秀樹, 中面哲也, 植村靖史
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Type I interferon-delivery by iPSC-derived myeloid cells elicits antitumor immunity via XCR1+ dendritic cells (2019)
  • Author(s): Zhang R, Tsuchiya N, Liu T, Kubo Y, Miyashita A, Fukushima S, Ihn H, Senju S, Endo I, Nakatsura T, Uemura Y.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Generation of proliferating professional antigen-presenting cells from induced pluripotent stem cells for cancer immunotherapy (2019)
  • Author(s): Mashima H, Zhang R, Kobayashi T, Liu T, Iwama T, Ohdan H, Nakatsura T, Uemura Y.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Type I interferon-delivery by iPSC-derived myeloid cells elicits antitumor immunity via XCR1+ dendritic cells. (2019)
  • Author(s): Fukuda K, Tsuchiya N, Liu T, Kubo Y, Miyashita A, Fukushima S, Ihn H, Senju S, Endo I, Nakatsura T, Uemura Y
  • Organizer: 17th International Congress of Immunology, Beijing China
  • Int'l Joint Research
• [Presentation] 人工多能性幹細胞に由来する1型IFN産生ミエロイド細胞を用いたがん免疫療法 (2018)
  • Author(s): 張 エイ, 土屋 伸広, 得光 友美, 千住 覚, 遠藤 格, 中面 哲也, 植村 靖史
  • Organizer: 癌免疫外科研究会
• [Presentation] Type 1 IFN-delivery by myeloid cells from induced pluripotent stem cells elicits systemic antitumor immunity via dendritic cells (2018)
  • Author(s): Rong Zhang, Nobuhiro Tsuchiya, Tianyi Liu, Yosuke Kubo, Satoshi Nakahara, Azusa Miyashita, Satoshi Fukushima, Hironobu Ihn, Satoru Senju, Itaru Endo, Tetsuya Nakatsura, Yasushi Uemura
  • Organizer: 日本免疫学会
• [Presentation] Cellular adjuvant properties and direct cytotoxicity in re-differentiated Vα24 invariant NKT cells from human induced pluripotent stem cells (2017)
  • Author(s): Rong Zhang, Syuichi Kitayama, Tianyi Liu, Tatsuaki Iwama, Tetsuya Nakatsura, Shin Kaneko, Yasushi Uemura
  • Organizer: 第36回 札幌国際がんシンポジウム
• [Presentation] Induction of CD8 T cell-mediated anti-tumor immunity by type 1 IFN-producing myeloid cell therapy (2017)
  • Author(s): Tatsuaki Iwama, Nobuhiro Tsuchiya, Rong Zhang, Tianyi Liu, Miwa Haruta, Yosuke Kubo, Azusa Miyashita, Satoshi Fukushima, Hironobu Ihn, Yasuharu Nishimura, Satoru Senju, Itaru Endo, Tetsuya Nakatsura, Yasushi Uemura
  • Organizer: 第36回 札幌国際がんシンポジウム
• [Presentation] IFNα産生ミエロイド細胞を用いたがん免疫療法 (2017)
  • Author(s): 岩間 達章、土屋 伸広、張 エイ、得光 友美、春田 美和、劉 天懿、吉川 聡明、澤田 雄、久保 陽介、宮下 梓、福島 聡、田久保 圭誉、阪上-沢野 朝子、宮脇 敦史、尹 浩信、西村 泰治、千住 覚、遠藤 格、中面 哲也、植村 靖史
  • Organizer: 第21回 日本がん免疫学会総会
• [Presentation] Induction of T cell-mediated anti-tumor immunity by type 1 IFN-producing myeloid cells (2017)
  • Author(s): IWAMA Tatsuaki, TSUCHIYA Nobuhiro, ZHANG Rong, LIU Tianyi, KUBO Yosuke, MIYASHITA Azusa, FUKUSHIMA Satoshi, IHN Hironobu, ENDO Itaru, SENJU Satoru, NAKATSURA Tetsuya, UEMURA Yasushi
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] 1型IFNを産生するiPS細胞由来ミエロイド細胞を用いたがん免疫療法 (2017)
  • Author(s): 張 エイ, 得光 友美, 土屋 伸広, 岩間 達章, 下村 真奈美, 澤田 雄, 遠藤 格,中面 哲也, 千住 覚, 植村 靖史
  • Organizer: 第46回 日本免疫学会学術集会