Activation of tumor immunity by metabolic reprogramming in liver cancer microenvironment
| Project/Area Number |
19H03644
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
Hino Keisuke 川崎医科大学, 医学部, 教授 (80228741)
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| Co-Investigator(Kenkyū-buntansha) |
仁科 惣治 川崎医科大学, 医学部, 准教授 (70550961)
山内 明 川崎医科大学, 医学部, 教授 (80372431)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2019: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | 腫瘍免疫 / がん微小環境 / 肝細胞癌 / Warburg効果 / ナノ粒子 / 2-depxy-D-glucose / 2DG-PLGA / 糖代謝 / Warburug効果 / 免疫担当細胞 / メタボローム解析 / 脂肪酸合成 / 解糖系抑制 / 免疫チェックポイント阻害剤 |
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| Outline of Research at the Start |
われわれはPoly(lactic-co-glycolic acid) (PLGA)ナノ粒子に糖代謝阻害剤である2-deoxy-D-glucose (2DG)を封入した2DG-PLGAを開発し、がん細胞特異的な糖代謝阻害剤のdrug delivery systemを開発した。そこで進行肝細胞癌に対する新たな治療戦略として、2DG-PLGAを用いた肝がん微小環境における代謝リプログラミング（糖代謝抑制）による腫瘍免疫賦活化を目指すtaranslational researchの基盤を確立する。
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| Outline of Final Research Achievements |
2-deoxy-D-glucose (2DG) encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-Nps) preferentially accumulated in liver tumor in mice. 2DG-PLGA-Nps induced cytotoxic effects (oxidative stress and endoplasmic reticulum stress) and antitumor immunity through enhanced T cell trafficking induced by increased chemokine production and decreased lactate production. Consequently, 2DG-PLGA-Nps inhibited liver tumor growth in mice.
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| Academic Significance and Societal Importance of the Research Achievements |
現在がんに対する免疫療法は注目を浴びているが、本研究はがん細胞のWarburg効果を抑制する2DGが新たにがん微小環境における抗腫瘍免疫を活性化することを初めて明らかにした点で学術的意義が高い。また2DGをナノ粒子に封入することでenhanced permeability retention効果を介して腫瘍特異的なdrug delivery systemを開発し、新たな肝がん治療薬の開発に繋がる可能性を示した点で社会的意義も高い。
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Report
(4 results)
Research Products
(20 results)
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[Journal Article] Final Results of TACTICS: A randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma2022
Author(s)
Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, Hino K, Tsumura H, Kuzuya T, Isoda N, Moriguchi M, Aino H, Ido A, Kawabe N, Nakao K, Wada Y, Ogasawara S, Yoshimura K, Okusaka T, Furuse J, Kokudo N, Okita K, Johnson P, Arai Y.
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Journal Title
Liver Cancer
Volume: in press
Related Report
Peer Reviewed / Open Access
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[Journal Article] Long-term phlebotomy successfully alleviated hepatic iron accumulation in a ferroportin disease patient with a mutation in SLC40A1: A case report.2021
Author(s)
Nishina S, Tomiyama Y, Ikuta K, Tatsumi Y, Toki Y, Kato A, Kato K, Yoshioka N, Sasaki K, Hara Y, Hino K.
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Journal Title
BMC Gastroenterology
Volume: 21(1)
Issue: 1
Pages: 111-111
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease2020
Author(s)
Okamoto, K. Koda, M. Okamoto, T. Onoyama, T. Miyoshi, K. Kishina, M. Matono, T. Kato, J. Tokunaga, S. Sugihara, T. Hiramatsu, A. Hyogo, H. Tobita, H. Sato, S. Kawanaka, M. Hara, Y. Hino, K. Chayama, K. Murawaki, Y. Isomoto, H.
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Journal Title
PLoS One
Volume: 15
Issue: 2
Pages: e0219412-e0219412
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice2019
Author(s)
Nishina, S. Yamauchi, A. Kawaguchi, T. Kaku, K. Goto, M. Sasaki, K. Hara, Y. Tomiyama, Y. Kuribayashi, F. Torimura, T. Hino, K.
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Journal Title
Cell Mol Gastroenterol Hepatol
Volume: 7
Issue: 1
Pages: 115-134
DOI
Related Report
Peer Reviewed
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[Journal Article] Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial2019
Author(s)
Kudo, M. Ueshima, K. Ikeda, M. Torimura, T. Tanabe, N. Aikata, H. Izumi, N. Yamasaki, T. Nojiri, S. Hino, K. Tsumura, H. Kuzuya, T. Isoda, N. Yasui, K. Aino, H. Ido, A. Kawabe, N. Nakao, K. Wada, Y. Yokosuka, O. Yoshimura, K. Okusaka, T. Furuse, J. Kokudo, N. Okita, K. Johnson, P. J. Arai, Y. Tactics study group
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Journal Title
Gut
Volume: -
Issue: 8
Pages: 1492-1501
DOI
NAID
Related Report
Peer Reviewed
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