The development of methods for inhibition of PD-L1 expression towards suppression of Epstein-Barr virus-related tumors

2023 Fiscal Year Final Research Report

• Project/Area Number: 18K07003
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Hyogo Medical University
• Principal Investigator: Matsuda Ikuo 兵庫医科大学, 医学部, 准教授 (50335452)
• Co-Investigator(Kenkyū-buntansha): 廣田 誠一 兵庫医科大学, 医学部, 教授 (50218856)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Keywords: Epstein-Barr virus / EBV / EBV陽性リンパ増殖性疾患 / EBV陽性腫瘍 / PD-L1 / M2型マクロファージ / B細胞 / 扁桃

Outline of Final Research Achievements

Epstein Barr virus-positive lymphoproliferative disorder (EBV-LPD) occurs in immunocompromised hosts. Novel therapies for EBV-LPD have been awaited. As with other tumors, EBV-LPD is infiltrated by protumoral M2-type macrophages that inhibit tumor-attacking activities of cytotoxic T cells. EBV-LPD and M2-type macrophages share PD-L1 expression. Tumor-infiltrating macrophages are differentiated from monocytes by colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor. In search of PD-L1 expression mechanisms shared by EBV-LPD and M2-type macrophages, I found that non-Hodgkin B-cell lymphomas (including EBV-LPD) were positive for immunohistochemistry using SP211, a novel monoclonal antibody for CSF1 receptor (CSF1R). The antibody-binding domain of SP211 can be exploited for antibody-drug conjugate or chimeric antigen receptor (CAR)-T cell therapy to control lymphoma cells and tumor-infiltrating macrophages derived from monocytes by a single agent.

Free Research Field

病理診断学

Academic Significance and Societal Importance of the Research Achievements

学術的意義は、B細胞と単球・macrophage系との生物学的共通性に着目する点である。EBV-LPDというB細胞系列とmacrophageが、本研究課題であるPD-L1発現機構を共有する要因に関して、B細胞と単球系の発生・分化は途中までIRF8を含む転写因子を共有することに気づいた。それが両系統でCSF1R発現を調べる動機となり、両系統で陽性となるマーカーSP211の発見につながった。SP211抗体は、抗体薬物複合体やchimeric antigen receptor (CAR)-T細胞へ応用すれば、EBV-LPD、B細胞リンパ腫とM2型macrophageを共通に制御するツールとなりうる。