Generation of TRAIL positive NK cells from hematopoietic stem cells / iPS cells in vitro for anti-HCC immunotherapy

• Project/Area Number: 24591880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Hiroshima University
• Principal Investigator: TANAKA Yuka 広島大学, 医歯薬保健学研究院(医), 准教授 (90432666)
• Co-Investigator(Kenkyū-buntansha): OHDAN Hideki 広島大学, 医歯薬保健学研究院(医), 教授 (10363061) ; ISHIYAMA Kohei 広島大学, 大学病院, 病院助教 (50437589)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: NK細胞 / 肝臓癌 / 細胞免疫療法

Outline of Final Research Achievements

We have previously reported that IL-2-stimulated CD56+ cells derived from the liver exert vigorous cytotoxicity against HCC. To differentiate NK cells, we incubated bone marrow-derived CD34+ hematopoietic progenitor cells in 5% serum-supplemented X-VIVO-15 medium containing SCF, Flt-3, IL-7, and IL-15. These NK cells expressed NKp46, a specific receptor of NK cells, and were phenotypically similar to resident NK cells, i.e. they expressed TRAIL, NKG2D, and CD226. The propagated NK cells produced IFN-γ. The propagated NK cells exhibited vigorous cytotoxicity against HCC cell lines by using 51Cr release assay. We have also developed a method to differentiate CD34+ hematopoietic progenitor cells from fibroblast-derived iPS cells. The use of NK cells for immunotherapy relies on the availability of large numbers of purified NK cells with optimal anti-HCC activities. This adaptive immunotherapy with these cells may be a promising modality to prevent the recurrence of HCC after hepatectomy.

Research Products

• [Journal Article] Quantitative effect of natural killer cell licensing on hepatocellular carcinoma recurrence after curative hepatectomy. (2014)
  • Author(s): Tanimine N, Tanaka Y, Kobayashi T, Tashiro H, Miki D, Imamura M, Aikata H, Tanaka J, Chayama K, Ohdan H.
  • Journal Title: Cancer Immunol Res. Volume: 2 Pages: 1142-1147
  • Peer Reviewed / Open Access
• [Journal Article] Fasting Enhances TRAIL-Mediated Liver Natural Killer Cell Activity via HSP70 Upregulation. (2014)
  • Author(s): Dang VT, Tanabe K, Tanaka Y, Tokumoto N, Misumi T, Saeki Y, Fujikuni N, Ohdan H.
  • Journal Title: PLoS One. Volume: 9 Issue: 10 Pages: e110748-e110748
  • DOI: 10.1371/journal.pone.0110748
  • Peer Reviewed / Open Access
• [Journal Article] Impact of alloimmune T cell responses on hepatitis C virus replication in liver transplant recipients. (2014)
  • Author(s): Tanaka Y, Ohira M, Tashiro H, Imamura M, Chayama K, Ohdan H.
  • Journal Title: Hum Immunol. Volume: 75 Issue: 12 Pages: 1259-1267
  • DOI: 10.1016/j.humimm.2014.09.006
  • Peer Reviewed / Open Access
• [Presentation] リモデリングNK 細胞によるHCV 感染抑制および制癌効果 (2014)
  • Author(s): 田中友加, 清水誠一, 大段秀樹.
  • Organizer: 第50回日本移植学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-09-10 – 2014-09-12
• [Presentation] Influence of adoptive immunotherapy employing allograft liver-resident lymphocytes on alloimmune responses (2014)
  • Author(s): Tanaka Y, Ohdan H
  • Organizer: WTC2014
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-07-26 – 2014-07-31
• [Presentation] 肝移植後活性化NK 細胞移入療法がT 細胞抗ドナー応答に与える影響解析 (2014)
  • Author(s): 田中友加,石山宏平, 大平真裕, 清水誠一, 井手健太郎, 尾上隆司, 小林剛, 田代裕尊, 大段秀樹.
  • Organizer: 第32回日本肝移植研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-03 – 2014-07-04
• [Presentation] Generation of NK cells from hematopoietic stem cells in vitro for anti-HCV and anti-HCC immunotherapy: Evaluation using human hepatocyte chimeric mice (2014)
  • Author(s): Shimizu S, Tanaka Y, Hotta R, Ohdan H.
  • Organizer: ILTS 2014
  • Place of Presentation: London, United Kingdom
  • Year and Date: 2014-06-04 – 2014-06-07
• [Presentation] Unlicensed NK Cells Differentiated from CD34+ Hematopoietic Progenitor Cells Exhibit Anti-HCC and Anti-HCV Activity (2013)
  • Author(s): Ryuichi Hotta, Yuka Tanaka, Seiichi Shimizu, Masahiro Ohira, Kohei Ishiyama, Nobuhiko Hiraga, Kazuaki Chayama, Hideki Ohdan
  • Organizer: American Transplant Congress2013
  • Place of Presentation: Seattle, America
• [Presentation] Hotta R, Ishiyama K, Ohira M, Igarashi Y, Tanaka Y, Onoe T, Ide K, Tashiro H, Ohdan H. Adoptive Immunotherapy with Donor Derived-Liver Natural Killer Cells Prevents HCC Recurrence after Liver Transplantation in Recipients Exceeding the Milan Criteria. (2012)
  • Author(s): Hotta R, Ishiyama K, Ohira M, Igarashi Y, Tanaka Y, Onoe T, Ide K, Tashiro H, Ohdan H
  • Organizer: American Transplantation Congress 2012
  • Place of Presentation: Boston, America