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A novel therapy to enhance the cancer immunity by remodeling tumor microenvironment in intrahepatic cholangiocarcinoma

Research Project

Project/Area Number 19K23905
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0901:Oncology and related fields
Research InstitutionTohoku University

Principal Investigator

Aoki Shuichi  東北大学, 大学病院, 特任助手 (30844451)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
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)
Keywords肝内胆管癌 / 腫瘍免疫 / 癌関連線維芽細胞 / CD8 T細胞 / 腫瘍血管 / 化学療法 / 癌微小環境 / 免疫治療 / 免疫チェックポイント阻害剤
Outline of Research at the Start

肝内胆管癌は未だ予後不良の癌であり、豊富な間質成分と癌細胞により作り出される癌微小環境こそが、癌生物像を規定する。申請者は、PlGFが癌細胞だけでなく、間質の主成分である癌関連線維芽細胞(CAFs)の活性化に重要な働きをしており、本研究では「抗PlGF療法によるCAFsの不活化が宿主の免疫応答を活性化させ、さらに免疫チェックポイント阻害剤の併用により免疫回避シグナルを直接遮断することで、更なる抗腫瘍効果を示す」ことを明らかにする。本研究により、肝内胆管癌において、CAFsと腫瘍免疫の両方を治療標的とした、全く新しい概念のstroma-targeting therapyが確立する。

Outline of Final Research Achievements

Intrahepatic cholangiocarcinoma (ICC) is a lethal liver malignancy with an increasing incidence. The success of programmed cell death 1 (PD-1) blockade in other cancers as a strategy of targeting immune checkpoint has brought great promise for ICC treatment. However, PD-1 blockade cannot enhance cytotoxic T lymphocyte infiltration and activation. This is likely due to other immunosuppressive cues in the ICC microenvironment, such as the abnormal vasculature and CAFs-induced secreted factors. We recently discovered that placental growth factor/neuropillin 1 (PlGF/Nrp1) pathway is activated in ICC and is a mediator of tumor growth and microenvironmental abnormalities. PlGF blockade resulted in tumor growth delay, reduced intratumoral hypoxia and increased cytotoxic T cell infiltration. We propose that anti-PlGF therapy could enhance the activity of chemotherapy with anti-PD-1 therapy by reprogramming the microenvironment of ICC to enhance delivery and reduce immunosuppression.

Academic Significance and Societal Importance of the Research Achievements

肝胆膵領域癌では、肝細胞癌において、抗VEGF療法による腫瘍内免疫環境のremodelingが腫瘍免疫の活性化をもたらし、抗VEGF療法とICBとの併用療法が、既に臨床に導入されている。胆道癌においても、本研究のように抗PlGF療法とICBとの併用療法の有効性が期待されている。しかしながら、本研究の結果からは、抗PlGF療法とICB併用療法が、生存期間の延長に寄与する可能性は少なく、一方で、現標準治療であるGC療法がICBとの併用により、抗腫瘍効果や生存期間の延長をもたらす可能性が高いことが示唆された。

Report

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

    (1 results)

All 2021

All Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] Placental growth factor promotes tumor desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma2021

    • Author(s)
      Shuichi Aoki
    • Organizer
      2021 Cholangiocarcinoma Foundation Annual Conference
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research

URL: 

Published: 2019-09-03   Modified: 2022-01-27  

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