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Basic research for the development of antitumor immunotherapy for neuroblastoma using immune checkpoint inhibition

Research Project

Project/Area Number 18K08550
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 55010:General surgery and pediatric surgery-related
Research InstitutionSaitama Medical University

Principal Investigator

Seiichiro Inoue  埼玉医科大学, 医学部, 准教授 (70431690)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsneuroblastoma / 免疫チェックポイント阻害 / dendritic cell / tumor infiltrating cell / ADCP / 神経芽腫 / 腫瘍浸潤リンパ球 / 腫瘍浸潤樹状細胞 / 小児神経芽腫 / 腫瘍免疫 / 自然免疫 / 免疫チェックポイント遮断 / マウス神経芽腫モデル / 神経芽細胞腫 / 腫瘍免疫学 / 免疫療法 / chemoimmunotherapy / 免疫checkpoint遮断
Outline of Final Research Achievements

The effect of immune checkpoint inhibitor on mouse neuroblastoma was investigated and host immune cells were analyzed in the tumor microenvironment. Neuro-2a cells were inoculated subcutaneously into mice, followed by intraperitoneal injection of antibodies targeting PD-1 and PD-L1. Tumor-infiltrating cells were analyzed. Growth of subcutaneous tumors was significantly suppressed, and PD-L1-expressing tumor cells were depleted by the antibody treatment. Neuro-2a cells opsonized by the anti-PD-L1 antibody were phagocytosed in the in vitro setting. In the treated tumor microenvironments, CD8+ lymphocyte and CD11c+ MHC II+ cells were accumulated. Immune suppressive effects of CD11b+Gr-1+ myeloid-derived suppressor cells by the administration of anti-PD-1 and PD-L1 antibodies were not observed. The possibility that co-administration of anti-PD-1 and anti-PD-L1 antibodies have a synergistic effect on inhibition of tumor growth and could be an effective therapy against neuroblastoma.

Academic Significance and Societal Importance of the Research Achievements

難治性進行小児神経芽腫に対する新たな免疫療法として、抗PD-1抗体PD-L1抗体の同時投与は抗腫瘍効果を示すことを確認し、pre clinical dataとして提供することができた。さらにこの抗体治療の効果のメカニズムには腫瘍に浸潤するリンパ球と貪食細胞が関与し、Antigen dependent cell phagocytosisの効果が有効に働いていることが示唆された。これらの結果は神経芽腫に対する新たな免疫治療の可能性を提示しながら、さらに腫瘍免疫学という基礎医学領域における新たな知見を示すことができた。これは腫瘍免疫学に関する発展に大きく貢献できる可能性があり意義が大きい。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Immune Checkpoint Inhibition Followed by Tumor Infiltration of Dendritic Cells in Murine Neuro-2a Neuroblastoma2020

    • Author(s)
      Seiichiro Inoue, Yutaka Horiuchi, Yumiko Setoyama, Yuta Takeuchi, Yoshifumi Beck, Takashi Murakami, Akio Odaka
    • Journal Title

      J Surg Res.

      Volume: 253 Pages: 201-213

    • DOI

      10.1016/j.jss.2020.03.059

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Combination of anti-PD-1/anti-PD-L1 antibodies with the distinct character exerts preferable anti-tumor immune cycle in a murine neuroblastoma model2020

    • Author(s)
      Inoue S, Horiuchi Y, Setoyama Y, Takeuchi Y, Murakami T, Odaka A,
    • Organizer
      52st congress of the International Society of Pediatric Oncology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 免疫チェックポイント遮断による腫瘍浸潤リ ンパ球(TIL)の抗腫瘍免疫誘導とそのメカニズム解 析-exhaustion maker 発現からみた TIL function の検討2020

    • Author(s)
      井上成一朗,堀内大,竹内優太,瀬戸山由美子, 別宮好文,村上孝,小高明雄
    • Organizer
      第57回日本小児外科学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Mobilization of multi-functional tumor infiltrating lymphocytes following co-administration of anti-PD-1/PD-L1 antibodies in a murine neuroblastoma model2019

    • Author(s)
      Inoue S, Horiuchi Y, Setoyama Y, Takeuchi Y, Beck T, Murakami T, Odaka A
    • Organizer
      51st congress of the International Society of Pediatric Oncology (Lyon, France)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] PD-L1陰性神経芽腫に対する免疫チェックポイント遮断による腫瘍浸潤リンパ球の抗腫瘍免疫誘導メカニズム2019

    • Author(s)
      井上成一朗、堀内大、竹内優太、.瀬戸山由美子、別宮好文、村上孝、小高明雄
    • Organizer
      第56回日本小児外科学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] TH-MYCN トランスジェニックマウスにおける腫瘍免疫環境の評価-導入遺伝子が免疫に与える影響2019

    • Author(s)
      竹内優太、井上成一朗、.瀬戸山由美子、別宮好文、小高明雄
    • Organizer
      第56回日本小児外科学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 重複免疫チェックポイント阻害による多機能性腫瘍浸潤リンパ球の誘導効果 -マウス神経芽腫モデルを用いた解析-2019

    • Author(s)
      井上成一朗、堀内大、.瀬戸山由美子、竹内優太、別宮好文、村上孝、小高明雄
    • Organizer
      第17回RCGM フロンティアシンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] Immune checkpoint inhibiton induce activated dendritic cell infiltration in PD-L1 negative tumor in mouse neuroblastoma model2018

    • Author(s)
      Inoue S, Setoyama Y, Takeutchi Y, Mori T, Odaka A, Beck Y.
    • Organizer
      50th congresscongress of the International Society of Pediatric Oncology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 小児外科におけるトランスレーショナルリサーチ適している研究分野とその活用法2018

    • Author(s)
      井上成一朗、小高明雄, 瀬戸山由美子、小山直基、森隆、別宮好文
    • Organizer
      第55回日本小児外科学会学術集会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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