2017-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647786摘要：PD-1 免疫檢查站蛋白抑制劑﹝immune checkpoint inhibitor﹞治療的初步臨床試驗結果顯示對於部分晚期肝細胞癌的病患有顯著療效，本計畫將進一步探討﹝1﹞肝細胞癌的分子異常對免疫微環境的可能調控機轉及與免疫治療療效的可能關聯；﹝2﹞如何透過併用其他免疫調控劑﹝例如TIM-3 或LAG-3 抑制劑﹞提高T 細胞的腫瘤毒殺效果與PD-1 抑制劑對肝細胞癌的療效；﹝3﹞抑制腫瘤相關巨噬細胞之免疫療法在肝癌治療的價值。β-catenin 基因的異常是肝細胞癌最常見的基因變異，而最近在黑色素細胞癌的研究指出，腫瘤細胞中β-catenin 基因的異常與腫瘤微環境中T 細胞的調控及免疫治療效果有密切關聯。本計畫將透過與台灣肝癌網﹝Taiwan Liver CancerNetwork, TLCN﹞組織庫的合作， 探討肝癌細胞中 β-catenin 以及其他基因的異常與腫瘤微環境中免疫調控機轉及免疫相關基因圖譜變異的關聯性，並將以正位﹝orthotopic﹞小鼠肝癌動物模式探討β-catenin 過度表現對於腫瘤免疫微環境的影響。T 細胞的活化與腫瘤毒殺效果是免疫治療成功的關鍵之一。過去研究指出TIM-3 與LAG-3 表現會抑制肝臟對於肝炎病毒的免疫反應，並有證據顯示合併TIM-3 或LAG-3 抑制劑可以提升PD-1 抑制劑的抗癌療效。本計畫將使用基因轉殖之肝癌細胞﹝Hepa 1-6.gp33 hepatoma cells﹞與動物實驗模式，探討合併TIM-3或LAG-3 抑制劑與PD-1 抑制劑，對於腫瘤微環境中由特定抗原誘發之T 細胞活化與腫瘤毒殺效果的調控機轉。腫瘤相關巨噬細胞具有免疫抑制、促進腫瘤侵襲與轉移等能力；在腫瘤微環境中常與T 細胞維持著彼消我長的關係。抑制腫瘤相關巨噬細胞之免疫療法已在許多癌症動物模式中誘發抗腫瘤活性，是免疫治療學的新興研究方向。本計畫將在不同免疫微環境（例如前述所建立之的β-catenin 野生型或過度表現型）之肝癌動物模式中探討單獨使用抑制腫瘤相關巨噬細胞之免疫療法或與PD-1 抑制劑併用的療效與抗腫瘤免疫反應。<br> Abstract: The anti-PD-1 immune checkpoint inhibitor has shown very promising anti-tumorefficacy in patients with advanced hepatocellular carcinoma (HCC). The present project willexplore (1) correlation between specific molecular abnormalities in HCC on the regulation ofimmune microenvironment and efficacy of immunotherapy; (2) combination strategies withimmune modulating agents (such as anti-LAG-3 and anti-TIM-3 agents) to enhance theactivation and killing activity of T cells by anti-PD1 therapy; (3) modulation oftumor-associated macrophages (TAMs) as novel immunotherapy for HCC.β-catenin mutation is the most common molecular aberration in HCC. A recent study inmelanoma indicated that β-catenin aberration can regulate the immune micro-environment andresponse to immunotherapy. By using HCC tumor samples from Taiwan Liver CancerNetwork tissue bank, this project will explore the effects of β-catenin and other molecularaberrations in HCC on the immune-related genomic features and regulatory mechanisms inHCC microenvironment. Murine orthotopic liver cancer models over-expressing β-cateninwill be developed to further clarify the regulatory mechanisms of β-catenin for anti-tumorimmunity in HCC.T cell activation and killing capability is critical for the success of immunotherapy.Previous studies indicated that expression of TIM-3 and LAG-3 can inhibit the anti-viralimmunity in the liver, and combination with anti-TIM-3 or anti-LAG-3 can improve theefficacy of anti-PD-1 therapy. In this project a genetically modified model (Hepa 1-6.gp33)will be used to test whether HCC tumor-specific CD8+ T cell immunity are impeded byTIM-3 or LAG-3 and whether the killing capability of tumor-specific CD8+ T cells can beenhanced by TIM-3 or LAG-3 inhibition.TAMs can inhibit anti-tumor immunity of T cells in the tumor microenvironment andpromote tumor invasion and metastasis. Inhibition of TAMs has been demonstrated inmany tumor models to have anti-tumor effects. This project will explore whetheranti-TAMs therapy, alone or in combination with PD-1 inhibitors, can enhance tumorgrowth suppression and anti-tumor immunity in animal models of HCC characterized withdifferent immune microenvironment (such as β-catenin wild-type and over expressionmutant).