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研究生:王昕妤
研究生(外文):Hsin-Yu Wang
論文名稱:探討Imiquimod為佐劑增強以免疫性細胞死亡為基礎之樹突細胞疫苗抑制腫瘤的可行性
論文名稱(外文):The Anti-tumoral Feasibility of Using Imiquimod as an Adjuvant to Enhance the Efficiency of ICD-based Dendritic Cell Vaccine
指導教授:謝政哲謝政哲引用關係
口試委員:吳俊穎陳春榮
口試日期:2017-06-28
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:74
中文關鍵詞:免疫性細胞死亡樹突細胞疫苗Imiquimod
外文關鍵詞:Immunogenic cell deathDendritic cell vaccineImiquimod
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在腫瘤的免疫性細胞死亡(ICD)的過程中,樹突細胞(dendritic cell, DC)扮演一個很重要的角色,凋亡的腫瘤細胞所釋出的損傷相關分子模式(DAMP)會與樹突細胞上的特異性受體結合,進而誘導樹突細胞的成熟與活化,而活化的樹突細胞會與T細胞作用,誘導專一性的免疫反應發生,進而抑制腫瘤的生長。已知Imiquimod(IMQ)與Resiquimod(REQ)皆為類鐸受體7(TLR7)的配合體且都具有抑制病毒與腫瘤增生的作用,特別是IMQ,有研究證實其可以活化並改善以樹突細胞為基礎的免疫治療效果,但是目前對於IMQ是否能誘導樹突細胞表現DAMP特異性受體的可能性仍然未知。故此研究的目的為探討IMQ是否能誘導樹突細胞活化並表現DAMP特異性受體,甚至是作為免疫佐劑去強化以ICD為基礎的樹突細胞疫苗治療效果。在腫瘤細胞層面,我們證實Mitoxantrone(MTX)這個常用於治療乳癌的化學藥物可以誘導4T1乳癌細胞株發生ICD,造成細胞凋亡並釋出DAMP。而在樹突細胞層面,我們證實IMQ與REQ皆可誘導漿細胞樣樹突細胞株(PMDC05)與骨髓樹突細胞(BMDC)活化相關蛋白和部分DAMP特異性受體的表現,尤其是IMQ,亦可增強BMDC遷移(migration)與吞噬(phagocytosis)的能力。最後在動物實驗層面,我們也證實在以MTX誘導4T1細胞ICD為基礎製成的樹突細胞疫苗確實有抑制腫瘤生長的效果,只是以IMQ處理的樹突細胞疫苗效果不如預期。不過以IMQ作為佐劑去增強疫苗的效果仍有其可行性,只是需搭配使用其他消除抑制作用的方法,例如抑制PD-L1的抗體,或許可改善目前IMQ的抗腫瘤效果。
Dendritic cells (DCs) play an important role in the process of tumor immunogenic cell death (ICD). The mainly characteristics of ICD are cells express damage-associated molecular patterns (DAMPs) during apoptosis. These DAMPs could be recognized by DCs through specific receptors, and promote DCs activation and maturation. Furthermore, tumor growth could be abolished by mature DCs-induced activation of tumor-specific T cell immune responses. Imiquimod (IMQ) and resiquimod (REQ) both are Toll-like receptor 7 (TLR7) ligands, contain the antitumor and antiviral activity. It has been reported that IMQ could activate DCs and improve DC-based immunotherapy for melanoma. However, whether the IMQ could induce the expression of DAMP specific receptor on DCs is still unknown. The purpose of this study is to investigate whether the IMQ could activate DCs and induce the expression of DAMP specific receptor on DCs, and even serve as an adjuvant to enhance the efficiency of ICD-based DC vaccine. Mitoxantrone (MTX), a chemical drug, is commonly used to treat breast cancer in clinical. In this study, we demonstrated that MTX promoted the expression of DAMPs to induce ICD response in 4T1 breast cancer cell lines. Additionally, we found that both IMQ and REQ induced the expression of DCs-activated protein and DAMP specific receptor partially in PMDC05 cells or bone-derived dendritic cells (BMDC). Furthermore, IMQ could also enhance the capability of migration and phagocytosis in BMDC. Finally, we also demonstrated that the ICD-based DC vaccine inhibited tumor growth in vivo. It should be worth to develop novel therapeutic strategies by utilizing ICD-based DC vaccine and has the feasibility of using IMQ as an adjuvant to enhance the efficiency of ICD-based DC vaccine. Our finding may extend beyond IMQ and MTX, as other monoclonal antibodies (anti-PD-L1) currently in clinical use, and they might provide a rationale for pursuing combination therapies of ICD-based DC vaccine with immune-checkpoint inhibitor and that can improve the anti-tumor activity of current IMQ therapy in clinical.
中文摘要......................................i
Abstract......................................ii
目錄..........................................iii
第一章 緒論..................................1

第一節........................................1

一、細胞死亡(Cell death)...........................................1
二、免疫性細胞死亡(Immunogenic cell death, ICD)....................2
三、Damage-associated molecular patterns (損傷相關分子模式,DAMP)..2
四、損傷相關分子模式(DAMP)與樹突細胞(Dendritic cells)..............4
五、免疫性細胞死亡(ICD)在癌症治療的應用............................6

第二節.............................................................7

一、類鐸受體(Toll-like receptors, TLRs)............................7
二、類鐸受體與樹突細胞.............................................8
三、Imiquimod(IMQ, R837)與Resiquimod(REQ, R848)....................9

第三節........................................10

一、乳癌(breast cancer).......................10
二、Mitoxantrone(米托蒽醌,MTX)...............10

第二章 研究目的..............................11

第三章 研究材料與方法........................12

一、細胞株培養(Cell Culture)..................12
二、藥物配置..................................13
三、西方墨點法(Western Blotting)..............14
四、流式細胞儀之分析(Flow cytometry)..........15
五、損傷相關分子模式(Damage-associated molecular patterns, DAMP)之偵測......17
六、樹突細胞遷移(migration)分析...............19
七、樹突細胞吞噬(phagocytosis)分析............21
八、樹突細胞疫苗處理之動物模式(The animal model of dendritic cell vaccine)..22
九、分析與統計方法............................23

第四章 結果..................................24

一、Mitoxantrone(MTX)誘導4T1乳癌細胞發生細胞凋亡.................24
二、Mitoxantrone(MTX)誘導4T1乳癌細胞釋出DAMP.....................24
三、Imiquimod或Resiquimod誘導漿細胞樣樹突細胞株(PMDC05)活化蛋白和部分DAMP特異性受體的表現..25
四、Imiquimod或Resiquimod誘導骨髓樹突細胞(BMDC)活化蛋白和大部分DAMP特異性受體的表現........26
五、MAPK路徑與DAMP特異性受體的關係(針對Erk探討)..................27
六、Imiquimod增強BMDC細胞遷移的能力..............................27
七、Imiquimod增強BMDC細胞吞噬的能力..............................28
八、Imiquimod無法有效的增強以ICD為基礎的樹突狀細胞疫苗效果.......29
九、Imiquimod可以誘導免疫抑制相關分子PD-L1的表現.................29

第五章 結論..................................31

第六章 討論..................................32

第七章 參考文獻..............................36

第八章 實驗結果圖............................45

圖一、MTX誘導4T1細胞株走向細胞凋亡..............45
圖二、MTX誘導4T1細胞株表現DAMP..................47
圖三、Imiquimod誘導PMDC05細胞株活化蛋白和部分DAMP特異性受體的表現...49
圖四、Resiquimod誘導PMDC05細胞株活化蛋白和部分DAMP特異性受體的表現..51
圖五、Imiquimod誘導BMDC活化蛋白和大部分DAMP特異性受體的表現…53
圖六、Resiquimod誘導BMDC活化蛋白和大部分DAMP特異性受體的表現...55
圖七、Erk路徑與DAMP特異性受體的關係.............57
圖八、Imiquimod增強BMDC細胞遷移的能力...........58
圖九、Imiquimod增強BMDC細胞吞噬的能力...........60
圖十、Imiquimod無法有效增強樹突細胞疫苗的效果...62
圖十一、Imiquimod誘導PD-L1表現..................64
圖十二、實驗結果總結............................65

第九章 附圖及附表............................67

附圖一、免疫性細胞死亡(ICD)過程示意圖.........67
附圖二、鈣網蛋白(CRT)釋出機制示意圖...........68
附圖三、樹突細胞(DC)來源示意圖................69
附圖四、人類類鐸受體種類示意圖................70
附圖五、類鐸受體反應路徑示意圖................71
附圖六、Imiquimod、Resiquimod的結構示意圖.....72
附圖七、Imiquimod藉由刺激樹突細胞而活化細胞性免疫反應以抑制腫的存活..73
附表一、抗體一覽表............................74
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