| Project/Area Number |
18K08018
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Osaka Medical and Pharmaceutical University |
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Principal Investigator |
Ohama Hideko 大阪医科薬科大学, 医学部, 非常勤医師 (60794782)
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| Co-Investigator(Kenkyū-buntansha) |
朝井 章 大阪医科薬科大学, 医学部, 准教授 (30622146)
小谷 卓矢 大阪医科薬科大学, 医学部, 特別職務担当教員(講師) (80411362)
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | Hepatocelullar carcinoma / macrophage / M２b単球 / GAS5遺伝子 / CCL1 / 肝細胞癌 / マクロファージ / GAS遺伝子 / GAS5 |
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| Outline of Final Research Achievements |
Hepatocellular carcinoma (HCC) is one of the most difficult cancers to deal with and 30,000 people die due to HCC every year. Treatment with immune checkpoint inhibitors that restore anti-tumor immunity has been recently indicated for HCC.
We have previously reported that M2b macrophage (Mf)/monocytes has the function of suppressing anti-tumor immunity in patients with HCC. When M2bMf/monocytes are eliminated, host anti-tumor immunity could be restored. However, this method uses CCL1 antisense oligodeoxynucleotides which could not efficiently suppress CCL1. In this study, M2b monocytes isolated from the blood of hepatocellular carcinoma patients, were treated with a gene therapy using Growth Arrest Specific 5, a long non-cording RNA that suppresses CCL1 gene expression. After the gene therapy, CCL1 productions from these cells were successfully decreased in vitro.
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| Academic Significance and Societal Importance of the Research Achievements |
肝細胞癌に対する免疫チェックポイント阻害剤（ICI）は効果的であるが万能ではない。我々はその原因の一つが、Mfにあると考えている。Mfは全身の80％が肝臓に存在し、肝臓の抗腫瘍免疫において非常に重要だが、肝細胞癌患者では腫瘍殺傷能を持たずまた抗原提示能も殆ど持たない上、他の腫瘍殺傷性１型細胞の出現を強力に妨害してしまうM2bMf/単球が優位に存在する。ICIは、このM2bMfに対し効果的に働かない。本研究のGAS5遺伝子療法は、M2bMf/単球のCCL1産生を効果的に抑制した。本治療はCCL1抑制からM2bMf消失を促し、最終的に肝臓の抗腫瘍免疫を回復させる新たな治療法となりうる可能性がある。
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