2023 Fiscal Year Final Research Report

Analysis of Pathogenesis Related to Immunological Profiles in the Hepatocellular Carcinoma Microenvironment using Hepatocellular Carcinoma Organoids.

Research Project

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Project/Area Number	21K07977
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 53010:Gastroenterology-related
Research Institution	Tokyo Medical and Dental University
Principal Investigator	Murakawa Miyako 東京医科歯科大学, 東京医科歯科大学病院, 助教 (20733851)
Co-Investigator(Kenkyū-buntansha)	朝比奈靖浩東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692) 柿沼晴東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30372444) 岡本隆一東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50451935)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	肝細胞癌 / オルガノイド / 薬物療法
Outline of Final Research Achievements	To analyze the mechanism of interaction between cancer cells and immune cells in the hepatocellular carcinoma (HCC) microenvironment and the drug response mechanism, we developed a 3D culture system of human iPS-Hep organoids as an experimental system.Furthermore, we started to construct disease organoids from human liver resection specimens, and succeeded in single-cell production from noncancerous parts. Analysis of molecular mechanisms involved in the response of HCC to therapy revealed that immunoregulatory monocytes are increased after TACE. Based on the results of the analysis of 213 HCC patients, we found that high CRP levels were associated with resistance to atezolizumab plus bevacizumab combination therapy. Based on these results, we initiated a comprehensive analysis of inflammatory cytokines and the hepatic microenvironment using a co-culture system of hepatic cancer organoids and hepatic stellate cells.
Free Research Field	肝臓病
Academic Significance and Societal Importance of the Research Achievements	ヒトiPS-Hepオルガノイドの3D培養系を確立したことで各種共培養系への展開が期待でき、肝内微小環境の解析に向けた基盤となる。また、患者肝検体非癌部からのsingle cell化成功は、目標とする患者個別の肝癌オルガノイド樹立に向けた一歩として学術的意義が高い。免疫チェックポイント阻害薬の治療効果に関わる分子機構、経時的免疫プロファイルの解析では期待された結果が出ず新たな実験を遂行中だが、臨床データから得られた知見を元にして炎症性サイトカインの網羅的解析を手がかりとした全身薬物療法の治療効果予測マーカーの創出を進めており、臨床で扱いやすいマーカーの同定は社会的・経済的に意義が大きい。