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Activation of tumor immunity by metabolic reprogramming in liver cancer microenvironment

Research Project

Project/Area Number 19H03644
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKawasaki Medical School

Principal Investigator

Hino Keisuke  川崎医科大学, 医学部, 教授 (80228741)

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)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
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)
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
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。

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.

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。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (20 results)

All 2022 2021 2020 2019

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (5 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 2 results)

  • [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.
    • Journal Title

      Liver Cancer

      Volume: in press

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD26/DPP4 as a Therapeutic Target in Nonalcoholic Steatohepatitis Associated Hepatocellular Carcinoma2022

    • Author(s)
      Nishina S, Hino K.
    • Journal Title

      Cancers

      Volume: 14 Issue: 2 Pages: 454-454

    • DOI

      10.3390/cancers14020454

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Correlation of hepatitis C virus-mediated endoplasmic reticulum stress with autophagic flux impairment and hepatocarcinogenesis2021

    • Author(s)
      Honma Yuichi、Miyagawa Koichiro、Hara Yuichi、Hayashi Tsuguru、Kusanaga Masashi、Ogino Noriyoshi、Minami Sota、Oe Shinji、Ikeda Masanori、Hino Keisuke、Harada Masaru
    • Journal Title

      Medical Molecular Morphology

      Volume: - Issue: 2 Pages: 108-121

    • DOI

      10.1007/s00795-020-00271-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines2021

    • Author(s)
      Nao Nishida, Masaya Sugiyama, Aiko Sakai, Katsushi Tokunaga, Masashi Mizokami et al.
    • Journal Title

      Sci Rep

      Volume: 11(1) Issue: 1 Pages: 3703-3703

    • DOI

      10.1038/s41598-021-82986-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Iron and liver cancer: an inseparable connection2021

    • Author(s)
      Hino Keisuke、Yanatori Izumi、Hara Yuichi、Nishina Sohji
    • Journal Title

      The FEBS Journal

      Volume: - Issue: 24 Pages: 7810-7829

    • DOI

      10.1111/febs.16208

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reduced Handgrip Strength Predicts Poorer Survival in Chronic Liver Diseases: A Large Multi-Center Study in Japan2021

    • Author(s)
      Nishikawa H, Shiraki M, Hiramatsu N, Hata K, Moriya K, Hino K, Koike K.
    • Journal Title

      Hepatol Res

      Volume: 51 Issue: 9 Pages: 957-967

    • DOI

      10.1111/hepr.13679

    • Related Report
      2021 Annual Research Report
  • [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.
    • Journal Title

      BMC Gastroenterology

      Volume: 21(1) Issue: 1 Pages: 111-111

    • DOI

      10.1186/s12876-021-01674-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice2021

    • Author(s)
      Sasaki Kyo、Nishina Sohji、Yamauchi Akira、Fukuda Kotaro、Hara Yuichi、Yamamura Masahiro、Egashira Kensuke、Hino Keisuke
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 11 Issue: 3 Pages: 739-762

    • DOI

      10.1016/j.jcmgh.2020.10.010

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [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.
    • Journal Title

      PLoS One

      Volume: 15 Issue: 2 Pages: e0219412-e0219412

    • DOI

      10.1371/journal.pone.0219412

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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.
    • Journal Title

      Cell Mol Gastroenterol Hepatol

      Volume: 7 Issue: 1 Pages: 115-134

    • DOI

      10.1016/j.jcmgh.2018.08.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [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
    • Journal Title

      Gut

      Volume: - Issue: 8 Pages: 1492-1501

    • DOI

      10.1136/gutjnl-2019-318934

    • NAID

      120006954908

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 肝細胞癌に対するナノ粒子を用いたがん細胞特異的解糖系阻害剤と腫瘍免疫応答効率化に関する検討2021

    • Author(s)
      仁科惣治、日野啓輔
    • Organizer
      第44回日本肝臓学会西部会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 新規抗腫瘍免疫活性化作用を標的としたがん特異的解糖系阻害剤による肝がん治療応用2021

    • Author(s)
      仁科惣治、日野啓輔
    • Organizer
      第57回日本肝臓学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] がん特異的解糖系阻害剤による肝細胞癌治療応用と免疫賦活化機構の解明2021

    • Author(s)
      仁科惣治、日野啓輔
    • Organizer
      第107回日本消化器病学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] がん特異的解糖系阻害剤による肝細胞癌治療応用と免疫賦活化機構の解明2020

    • Author(s)
      仁科惣治、佐々木 恭、日野啓輔
    • Organizer
      第56回日本肝臓学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Anti tumor effects of 20deoxy-D-glucose encapsulated PLGA nanoparticles against hepatocellular carcinoma in term of tumor immunity2019

    • Author(s)
      Sasaki K, Nishina S, Yamauchi A, Hara Y, Fukuda K, Hino K
    • Organizer
      Annual Meeting of the American Association for the Study of Liver Diseases
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] ケモカイン産生促進剤、免疫チェックポイント阻害剤抵抗性癌治療薬及び抗腫瘍免疫賦活剤2020

    • Inventor(s)
      日野啓輔、仁科惣治、佐々木 恭、福田宏太郞
    • Industrial Property Rights Holder
      日野啓輔、仁科惣治、佐々木 恭、福田宏太郞
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 医薬組成物及び腫瘍免疫促進剤2020

    • Inventor(s)
      日野啓輔、仁科惣治、佐々木 恭、福田宏太郞
    • Industrial Property Rights Holder
      日野啓輔、仁科惣治、佐々木 恭、福田宏太郞
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 医薬組成物及び腫瘍免疫活性促進剤2019

    • Inventor(s)
      仁科 惣治 日野  啓輔 佐々木 恭 福田 宏太郎
    • Industrial Property Rights Holder
      仁科 惣治 日野  啓輔 佐々木 恭 福田 宏太郎
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Acquisition Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] ケモカイン産生促進剤、免疫チェックポイント阻害剤抵抗性癌治療薬及び抗腫瘍免疫賦活剤2019

    • Inventor(s)
      佐々木 恭、仁科惣治、日野啓輔
    • Industrial Property Rights Holder
      佐々木 恭、仁科惣治、日野啓輔
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-048743
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas

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Published: 2019-04-18   Modified: 2023-01-30  

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