| Project/Area Number |
21K15954
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
Kubo Tomohiro 札幌医科大学, 医学部, 助教 (00634669)
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | CIML NK cell / 選択的Class Ⅱa HDAC阻害薬 / 肝細胞癌 / NK細胞 / HDAC阻害剤 |
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| Outline of Research at the Start |
肝癌に対する有効性の高い治療法を開発する鍵として、免疫細胞の一つであるNK細胞とマルチキナーゼ阻害薬以外の機序による新規治療の開発に着目し、本研究では、複数のサイトカイン刺激により作成した、強力な抗腫瘍効果のあるCytokine Induced Memory Like NK細胞の肝癌への応用と肝癌に高発現する選択的HDAC Class Ⅱaの病勢関与に焦点をあて、両者の併用による新規肝癌治療の可能性を追求する。
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| Outline of Final Research Achievements |
We evaluated that the antitumor effects of CIML NK cells and their combination with selective inhibitors of HDAC Class IIa, which is highly expressed in hepatocellular cell carcinoma and involved in the regulation of gene expression, in hepatocellular cell carcinoma cell lines. CIML NK cells showed higher cytotoxic activity in hepatocellular cell carcinoma cell lines compared to control NK cells (IL-2 stimulation only). Next we examined changes in gene expression of hepatocellular cell carcinoma cell lines exposure to selective Class IIa HDAC inhibitors, we found that ULBP1 and B7-H6 gene expression, which are ligands for NK cell activation receptors, were decreased. and the cytotoxic activity of CIML NK cells in hepatocellular cell carcinoma cell lines was reduced by concomitant use of selective Class IIa HDAC inhibitors.
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| Academic Significance and Societal Importance of the Research Achievements |
CIML NK細胞による免疫療法は、肝細胞癌に対しても高い抗腫瘍効果を示し、新たな治療戦略の一つとなる可能性が示唆されるが、今後、in vivoマウスモデルでの抗腫瘍効果の検討や癌微小環境内においてCIML NK細胞の細胞傷害活性が維持されるかなどについてさらにこの研究を発展させていく必要がある。一方で選択的 Class IIa HDAC阻害薬はCIML NK細胞の細胞傷害活性を減弱させたため、CIML NK細胞の効果を増強する他のepigenetic drugの探索が必要である。
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