Mechanism of immune cell inactivation using glioma stem cells and iPS cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K08962
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: University of Tsukuba
• Principal Investigator: Ishikawa Eiichi 筑波大学, 医学医療系, 教授 (30510169)
• Co-Investigator(Kenkyū-buntansha): 松田 真秀 筑波大学, 医学医療系, 講師 (30614333) ; 坪井 康次 筑波大学, 医学医療系, 名誉教授 (90188615)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: 悪性神経膠腫 / 免疫療法 / PD-L1 / マクロファージ

Outline of Final Research Achievements

To search for factors that influence recurrence and prognosis of glioblastoma, we characterized a chemotherapy-resistant stem cell line and tested the effects of immunotherapy using a mouse model. The stem cells expressed the immune checkpoint molecule PD-L1. In addition, expression of some factors related to macrophage induction and differentiation are observed. The combination of anti-PD-L1 antibody and immunosuppressive macrophage inhibitors in a mouse subcutaneous tumor model prolonged survival time by suppressing macrophage infiltration after immunotherapy. Also in human glioblastoma, infiltrating macrophages were increased in early recurrent tissues after immunotherapy, suggesting that they may contribute to the recurrence of the disease. Based on these experiences, we made research papers and review articles.

Free Research Field

脳神経外科

Academic Significance and Societal Importance of the Research Achievements

化学療法耐性グリオーマ幹細胞は免疫チェックポイント分子のPD-L1を発現しており、これに加えてマクロファージの誘導、分化に関する因子の発現が確認されたことから、膠芽腫標準治療後の再発の一因として治療抵抗性の幹細胞による免疫抑制微小環境の形成が影響していることが明らかとなった点は、初めての報告であり今後の悪性神経膠腫への薬剤開発の発展に寄与する。また、マウス皮下腫瘍モデルにおいて抗PD-L1抗体と免疫抑制性マクロファージ阻害剤を併用効果についても、初めての知見であり学術的意義がある。