Abstract
摘要:肝癌防治一直是一個重要課題。對於肝癌治療反應不佳且易於復發近來被認為可能與腫瘤免疫抑制有關,而降低腫瘤免疫抑制,有潛力成為抗癌方法。目前常使用的無線電射頻消融(RFA),在治療後造成的腫瘤殘骸有可能形成腫瘤抗原,應該有誘發抗腫瘤免疫反應的機會,然而研究證實腫瘤附近的浸潤細胞如骨髓延伸抑制性細胞(MDSCs)或M2 巨噬細胞會抑制免疫反應。了解特殊免疫細胞在肝癌中的角色及分布比率,並改變它們的特性或許有機會成為目前治療方法的輔助療法。我們的研究發現一個促進轉錄因子C/EBPα 表現的短活化核糖核酸能縮減腫瘤並增進肝臟功能,同時在前期研究,我們也發現C/EBPα 能調節免疫細胞之成熟與增殖,所以本計畫將結合RFA 與C/EBPα 治療,研究RFA 和這些細胞對腫瘤免疫的影響,是否可以誘導全身性免疫反應,當結合上C/EBPα 治療時,是否會減少MDSCs 作用,改變巨噬細胞種類,提高RFA 治療效果,進而達到防止局部復發和轉移的功效。本研究首先將分析肝癌動物中,MDSCs 以及M1、M2 巨噬細胞的分布情形,驗證腫瘤的生長是不是會改變局部以及全身性的相關免疫。其次目標為進一步研究分別以RFA 或C/EBPα 短活化核糖核酸來處理這幾種不同的肝癌模式動物,看看是否能影響細胞的分布以增強抗腫瘤免疫能力。最後目標為評估結合RFA 與C/EBPα 治療進行臨床前免疫治療研究。執行本計畫可能產生對社會、經濟、學術發展等面向的預期影響性:本計畫中我們希望能拓展癌症治療方法,進一步改變腫瘤免疫微環境的方法達到更好的療效。結合射頻燒灼術與C/EBPα 短活化核糖核酸兩種治療法,希望能增加腫瘤的壞死與減少腫瘤的復發。最終,我們期望此聯合療法能更有利於肝癌病人的治療。
Abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide.Hence, prevention and treatment of HCC are of great concern. The characteristics of HCC about poorresponse to current treatment and tendency to be recurrent was supposed to be related to immune evasionrecently, and the immunotherapy to increase anti-tumor immunity maybe a promising tool for HCC.Radiofrequency ablation (RFA) has developed as reliable options for HCC. Previous reports have shownthat RFA not only destroys tumors but also generates a tumor antigen source that stimulates antitumorimmunity and enhances host immune responses. However, the anti-tumor immunity is still not so prominent,and that was suspected to be related to the immune inhibition by local infiltrating immunocytes such asmyeloid-derived suppressor cells (MDSCs) or M2 macrophage. MDSCs are one of the critical players inimmunosuppression induced in infection and malignancy. Several researches have reported that MDSCsaccumulate in peripheral blood and tumor of HCC patients and cause immune cell dysfunction to supportingmetastasis. Therapeutic modulations of tumor-induced MDSCs will be a possible weapon for HCC.In addition to MDSCs, macrophages are gradually known to be related to inhibition of anti-tumorimmunity. Macrophage contents heterogeneous cell populations with different functions depending onpolarization status. Macrophages can be divided into classically activated inflammatory M1 macrophages andalternatively activated M2 anti-inflammatory macrophages. A recent study has shown that M2 macrophagespromote tumor growth and metastasis in an orthotopic liver cancer model. Therefore, understanding thedistribution of M1 and M2 macrophages in HCC and reprogramming macrophages to switch their phenotypecould provide therapeutic strategies.Our recent study demonstrated the first evidence that saRNA-oligonucleotide which enhance expressionof a transcriptional regulator C/EBPα could reduce tumor burden and improves liver function in the animalmodel, and we also found C/EBPα could modulate the maturation and proliferation of myelocyte. There seemto be potential to augment immune response after RFA by adjuvant treatment of C/EBPα.The project described here propose that RFA in combination with C/EBPα-saRNA treatment mightinduce a systemic immune response and, therefore, might enhance the efficacy of RFA treatment andprotection against local recurrences and the expansion of metastasis. Aim 1 is to evaluate the expressionlevels of MDSCs, M1, and M2 macrophages in different HCC animal models. Aim 2 is to examine whethertreatment with either C/EBPα-saRNA or RFA could convert the distribution of MDSCs, M1 and M2macrophages. Aim 3 is to estimate whether the combinational therapy with C/EBPα-saRNA following RFAcould further eliminate MDSCs, alter M1, M2 macrophages distribution and enhance the abscopal effect.Potential contribution to academics, national developments, or other applications:The project described here represent an underdeveloped border in cancer therapeutics and outline amethod that we hope to alter the tumor immune microenvironment. Combination therapy involvingC/EBPα-saRNA and RFA could be beneficial in terms of increasing tumor necrosis and reducing therecurrence rate. Ultimately, we expect that this combination therapy might, therefore, be of benefit to HCCpatients.
Keyword(s)
肝癌
免疫治療
巨噬細胞
骨髓衍生抑制性細胞
無線電射頻消融
hepatocellular carcinoma (HCC)
immunotherapy
macrophages
myeloid-derived suppressor
cells (MDSCs)
radiofrequency ablation (RFA)