2021 Fiscal Year Final Research Report

The elucidation of mechanism underlying pancreatic cancer progression by complement and secreted proteins in tumor microenvironment.

Research Project

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Project/Area Number	19H03725
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Chiba University
Principal Investigator	Takano Shigetsugu 千葉大学, 医学部附属病院, 講師 (20436380)
Co-Investigator(Kenkyū-buntansha)	酒井望千葉大学, 医学部附属病院, 助教 (70436385) 大塚将之千葉大学, 大学院医学研究院, 教授 (90334185) 鈴木大亮千葉大学, 大学院医学研究院, 助教 (90422229) 賀川真吾千葉大学, 医学部附属病院, 助教 (90507302) 佐藤守千葉大学, 医学部附属病院, 特任准教授 (20401002) 吉富秀幸千葉大学, 大学院医学研究院, 准教授 (60375631)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	膵癌 / 補体 / バイオマーカー / 癌周囲微小環境 / 腫瘍浸潤リンパ球
Outline of Final Research Achievements	Complement plays pivotal roles in promoting or suppressing cancer progression. We elucidated the functional roles of C4b-binding protein α-chain (C4BPA) in pancreatic ductal adenocarcinoma (PDAC). We assessed stromal C4BPA, CD40, and the number of CD8+ TILs in resected human PDAC tissues. Immunohistochemical analysis revealed that high stromal C4BPA and CD40 was associated with favorable PDAC prognosis. Stromal C4BPA strongly correlated with the number of CD8+ TILs. In in vitro experiments, flow cytometry revealed that recombinant human C4BPA stimulation increased CD8+ T cell numbers in peripheral blood mononuclear cells (PBMCs). mC4BPA peptide increased the number of CD8+ tumor-infiltrating lymphocytes surrounding PDAC tumors in vivo. In a preclinical study, GnP/ICBs/mC4BPA peptide treatment, but not GnP treatment, led to the accumulation of a greater number of CD8+ T cells in the periphery of PDAC tumors and to greater tumor regression than did control treatment.
Free Research Field	肝胆膵外科
Academic Significance and Societal Importance of the Research Achievements	今まで殆ど報告のなかった、補体の１因子であるC4BPAの膵癌進展を阻害するmechanismについての研究であるため、非常に新規性があり将来の新しい治療ターゲットとして期待ができる研究成果となった。これらの成果は国内の学会で、主に口演や上級演題での報告や、High impactなJournalにもaccept/publishされており、今後のcomplement-based immunomodulation therapyの一つの知見として国内外へ広く発信できたと考える。