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Expansion of Th1-like gamma delta T cells by new generation IMiDs and their cytotoxicity against myeloma progenitors

Research Project

Project/Area Number 17K09956
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionThe University of Tokushima

Principal Investigator

MIKI Hirokazu  徳島大学, 病院, 講師 (50511333)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
KeywordsγδT細胞 / 多発性骨髄腫 / 免疫調節薬 / ガンマデルタT細胞 / HDAC阻害薬 / Pim阻害薬 / γδT細胞 / HM1.24 / 骨髄腫
Outline of Final Research Achievements

After PBMCs isolated from normal donors were incubated for one week with Zol and IMiDs (LEN or POM) in combination, γδT cells were robustly expanded. The expanded γδT cells expressed intracellular IFN-γ but not Foxp3 along with increased surface expression of NKG2D and DNAM-1, indicating induction of Th1-like γδT cells. Interestingly, the expanded γδT cells also markedly minimized the sizes of side populations in RPMI8226 and KMS-11 cells, and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice, suggesting targeting a drug-resistant clonogenic MM cells. SMI-16a,Pim inhibitor, upregulated surface expression of HSP70 on MM cells. Pretreatment with SMI-16a further potentiate the cytotoxic activity of γδT cells against MM cells. Combination with novel anti-MM agents warrants further study in terms of further enhancement of anti-MM effects with the ex-vivo expanded Th1-like γδT cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、Th1機能を増強させた抗腫瘍活性のより強いγδT細胞を体外で大量に誘導するため合成IPPによるγδTCRの直接刺激と免疫腑活作用を有する抗骨髄腫薬(IMiDs)という新規の併用法を用いる点、誘導したTh1様γδT細胞の抗腫瘍効果を高まるためにADCC活性を惹起する新規抗骨髄腫薬を用いる点、γδT細胞を腫瘍残存部で活性化させ残存腫瘍細胞を駆逐しようとする点に独創性を有している。免疫調節薬を用い癌前駆細胞や癌幹細胞のγδT細胞への感受性を高める試みはこれまでになく、これらの研究により得られる成果は、悪性腫瘍全般に応用可能な新規免疫療法として発展することが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (8 results)

All 2019 2018 2017

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (3 results) (of which Invited: 2 results)

  • [Journal Article] PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ.2019

    • Author(s)
      Iwasa Masami、Harada Takeshi、Oda Asuka、Bat-Erdene Ariunzaya、Teramachi Jumpei、Tenshin Hirofumi、Ashtar Mohannad、Oura Masahiro、Sogabe Kimiko、Udaka Kengo、Fujii Shiro、Nakamura Shingen、Miki Hirokazu、Kagawa Kumiko、Ozaki Shuji、Abe Masahiro
    • Journal Title

      Oncotarget

      Volume: 10 Issue: 20 Pages: 1903-1917

    • DOI

      10.18632/oncotarget.26726

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Correlation between high serum alkaline phosphatase levels and denosumab-related hypocalcemia in patients with multiple myeloma.2019

    • Author(s)
      Miki H, Nakamura S, Oura M, Hamano H, Ikuta K, Okada N, Okamoto Y, Sogabe K, Takahashi M, Iwasa M, Udaka K, Harada T, Kurahashi K, Fujii S, Yoshida S, Kagawa K, Endo I, Aihara KI, Abe M.
    • Journal Title

      British Journal of Haematology

      Volume: in press Issue: 2 Pages: 355-358

    • DOI

      10.1111/bjh.15837

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effective impairment of myeloma cells and their progenitors by hyperthermia.2018

    • Author(s)
      Hirokazu Miki, Shingen Nakamura, Asuka Oda, Hirofumi Tenshin, Jumpei Teramachi, M. Hiasa, A. Bat-Erdene, Y. Maeda, M. Oura, M. Takahashi, M. Iwasa, T. Harada, S. Fujii, K. Kurahashi, S. Yoshida, K. Kagawa, I. Endo, K. Aihara, M. Ikuo, K. Itoh, Koichiro Hayashi, Michihiro Nakamura, Masahiro Abe
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 12 Pages: 10307-10316

    • DOI

      10.18632/oncotarget.23121

    • NAID

      120006576960

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.2018

    • Author(s)
      Fujii S, Nakamura S, Oda A, Miki H, Tenshin H, Teramachi J, Hiasa M, Bat-Erdene A, Maeda Y, Oura M, Takahashi M, Iwasa M, Endo I, Yoshida S, Aihara KI, Kurahashi K, Harada T, Kagawa K, Nakao M, Sano S, Abe M.
    • Journal Title

      British Journal of Haematology

      Volume: 180(2) Issue: 2 Pages: 246-258

    • DOI

      10.1111/bjh.15033

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects2017

    • Author(s)
      Tenshin Hirofumi、Teramachi Jumpei、Tanaka Eiji、Matsumoto Toshio、Abe Masahiro (他16人中2番目)
    • Journal Title

      Blood Advances

      Volume: 1 Issue: 24 Pages: 2124-2137

    • DOI

      10.1182/bloodadvances.2017008813

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 高ALP血症は骨病変を有する骨髄腫患者のデノスマブ関連低カルシウム血症の発症予測因子である2018

    • Author(s)
      三木浩和
    • Organizer
      日本骨髄腫学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 多発性骨髄腫における溶骨性病変の発症機序とその治療2017

    • Author(s)
      三木浩和
    • Organizer
      第57回日本リンパ網内系学会総会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] ALアミロイドーシスに対する治療戦略2017

    • Author(s)
      三木浩和
    • Organizer
      第5回日本アミロイドーシス研究会学術集会
    • Related Report
      2017 Research-status Report
    • Invited

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Published: 2017-04-28   Modified: 2021-02-19  

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