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

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23905
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Tohoku 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
• 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

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.

Free Research Field

腫瘍免疫

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。