2022 Fiscal Year Final Research Report

the elucidation of mechanism underlying C4BPA-CD40 axis in pancreatic cancer progression

Research Project

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Project/Area Number	20K09073
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Chiba University (2020, 2022) International University of Health and Welfare (2021)
Principal Investigator	Sasaki Kosuke 千葉大学, 大学院医学研究院, 特任助教 (90836181)
Co-Investigator(Kenkyū-buntansha)	高野重紹千葉大学, 医学部附属病院, 講師 (20436380) 大塚将之千葉大学, 大学院医学研究院, 教授 (90334185) 賀川真吾千葉県がんセンター(研究所), 肝胆膵外科, 主任医長 (90507302)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	膵癌 / 補体 / バイオマーカー / C4BPA / CD40
Outline of Final Research Achievements	C4BPA was identified as a novel biomarker for PDAC by comprehensive protein analysis of pre- and postoperative sera of PDAC patients. Furthermore, we clarified that fucosylated C4BPA was significantly higher in PDAC patients than in healthy and pancreatitis patients. Fluorescent immunostaining of resected PDAC tissue revealed that stromal C4BPA and CD40 were co-expressed around the cancer cells, and immunohistostaining revealed that the prognosis was significantly better in patients with high expression groups of C4BPA and CD40. C4BPA expression was positively correlated with number of CTLs. In PDAC cell lines, C4BPA specifically acted on CD40 for cell proliferation. In preclinical studies using orthotopic transplantation model mice, the GnP/ICBs/mC4BPA peptide treatment induced a greater number of CTLs in the peripheral of PDAC tumors and the tumor regression than did the control treatment. C4BPA-CD40 Axis could be a novel therapeutic target for pancreatic cancer.
Free Research Field	消化器外科
Academic Significance and Societal Importance of the Research Achievements	近年、腫瘍微小環境内における補体の役割については注目されつつあるものの、癌進展機構における補体の機能やそのメカニズムについては殆ど解明されていない。今回、補体因子C4BPAに着目し、C4BPAの膵癌における機能について解明するとともに、免疫療法における新規治療標的のひとつであるCD40との相関を明らかとした点で将来の治療ターゲットとして期待できる研究成果となった。これらの研究成果は国内外の学会で口演や上級演題による発表を行い、High impactなjournalにもpublishされており、今後の補体と癌免疫の分野における一つの知見として国内外へ広く発信できたと考える。