2024 Fiscal Year Final Research Report

Extracellular signals in cancer stemness and immune evasion in hepatocellular carcinoma

Research Project

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Project/Area Number	22K08850
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	Yamaguchi University
Principal Investigator	Tsunedomi Ryouichi 山口大学, 医学部附属病院, 講師 (10420514)
Co-Investigator(Kenkyū-buntansha)	永野浩昭山口大学, 大学院医学系研究科, 教授 (10294050) 松隈聰山口大学, 医学部附属病院, 助教 (10634743) 前田訓子山口大学, 医学部附属病院, 助教 (10738876) 西山光郎山口大学, 医学部附属病院, 助教 (50714614) 新藤芳太郎山口大学, 医学部附属病院, 助教 (70749811)
Project Period (FY)	2022-04-01 – 2025-03-31
Keywords	がん
Outline of Final Research Achievements	In this study, we focused on elucidating the molecular mechanisms by which cancer stem-like sphere cells (CSLCs) derived from hepatocellular carcinoma evade natural immunity mediated by NK cells. CSLCs exhibited high expression of immunosuppressive membrane-bound molecules such as PD-L1, PD-L2, and CEACAM1, while showing reduced expression of NK cell-activating ligands MICA and MICB. Furthermore, CSLCs demonstrated resistance to NK cell-mediated cytotoxicity and exhibited enhanced tumorigenic potential in a mouse model. Soluble MICA and secreted exosomes were found to be involved in these immune evasion mechanisms. Analysis of exosomes derived from CSLCs also revealed differential expression of miRNA/mRNA clusters associated with cell motility.
Free Research Field	腫瘍学
Academic Significance and Societal Importance of the Research Achievements	本研究は、肝癌の再発や転移の主因とされる癌幹細胞様浮遊細胞塊（CSLC）が持つ免疫逃避能の分子基盤を解明し、新たな治療標的候補としてPD-L1, L2に加えて、細胞外因子としてsMICA、エクソソーム内microRNAの意義を明らかにした。特に、CSLCにおけるNK細胞からの免疫逃避はこれまで詳細に検討されておらず、本研究はその先駆的成果である。今後、これらの知見は免疫療法と組み合わせた個別化医療の進展に寄与し、肝癌患者の予後改善や再発防止に大きく貢献することが期待される。