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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 莊曜宇(Eric Y. Chuang) | |
dc.contributor.author | Shih-Han Huang | en |
dc.contributor.author | 黃詩涵 | zh_TW |
dc.date.accessioned | 2021-06-17T04:25:52Z | - |
dc.date.available | 2021-08-21 | |
dc.date.copyright | 2018-08-21 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-08-14 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70324 | - |
dc.description.abstract | 肺癌是目前全球癌症死亡的主要原因,經過傳統治療後肺癌患者的五年存活率僅12%左右。而在治療癌症的方法中有一種新的革命性療法稱為免疫療法,它是利用自身的免疫系統來檢測和破壞異常細胞以防止癌症發展。免疫療法的優點是能夠針對腫瘤而誘導免疫細胞的毒殺特異性。因此,找出具有良好免疫調節性質能夠對抗癌症的指標基因對免疫療法的發展至關重要。而在我們實驗室之前的研究顯示Semaphorin 6A(SEMA6A)在肺癌組織中表現量是下降的。此外,在過去的研究中Semaphorin家族相關的免疫調節性質已被報導。然而,SEMA6A與免疫之間的影響目前仍不清楚。在我們的初步研究中,我們發現當老鼠脾臟細胞與人肺癌細胞株(H1299)中大量表現SEMA6A共同培養時,SEMA6A會使T細胞的比例和脾臟細胞的遷移能力增強。此外,通過Kaplan-Meier存活曲線分析了擁有相同受體的SEMA6A和SEMA3A對患者存活率的影響時發現,當SEMA6A低表達和SEMA3A高表達的情況下,患者存活率呈現顯著性下降(p<0.01),而在其他SEMA6A和SEMA3A組合的情況則對患者生存沒有顯著影響。因此,本研究中將探討SEMA6A的免疫功能及其與SEMA3A在免疫中的相互作用。為了避免大量的內生性SEMA3A的影響,先將小鼠肺癌細胞株(KLN205)的SEMA3A表現抑制,再進行SEMA6A免疫功能的研究。實驗是將分離出之小鼠脾臟細胞跟不同處理之KLN205細胞共同培養,共分為四組:對照組、SEMA6A大量表現組、外加SEMA3A蛋白組、SEMA6A大量表現並外加SEMA3A蛋白組。共培養三或九天後,比較各組間不同免疫細胞移動、增生、毒殺能力。並以脾臟細胞基因表現狀況預估可能受到SEMA6A及SEMA3A影響的免疫細胞。結果顯示,在共培養九天後,SEMA6A相較於對照組可以增強脾臟細胞的細胞數及遷移能力,且能夠降低調節型T細胞的增生能力。此外,SEMA6A亦可減輕SEMA3A抑制毒殺型T細胞及自然殺手細胞毒殺能力的效果。最後,我們還將共培養後的脾臟細胞使用微陣列分析基因表現狀況,並以ImmQuant和GSEA兩個軟體來預測其他可能還會由SEMA6A和SEMA3A所調控的免疫細胞種類。預測結果指出,SEMA6A可誘導樹突細胞的活性,並可減低SEMA3A對B細胞的抑制作用。但SEMA6A及SEMA3A對M1、M2巨噬細胞皆無明顯作用。綜合以上的結果,SEMA6A可能單獨刺激,或通過降低SEMA3A的免疫抑制作用增強不同的抗癌免疫反應,因此SEMA6A應可成為未來有潛力的癌症免疫治療基因。 | zh_TW |
dc.description.abstract | Lung cancer is the leading cause of cancer death worldwide, and the 5-year survival of lung cancer patients is only 12% after traditional treatments. A revolutionary therapy of cancer called immunotherapy uses the natural capability of immune system to detect and destroy abnormal cells and to prevent cancer development. Since the purpose of immunotherapy is enhancing cytotoxic specificity for tumors, it is important for immunotherapy to find a potential target gene that possesses positive immunomodulatory properties against cancer. Our previous study indicated that semaphorin 6A (SEMA6A) was down-regulated in lung cancer tissue. Moreover, semaphorin family was reported for its immunoregulatory properties in the past studies. However, the effect of SEMA6A on immunity is still unclear. In our pilot study, we isolated mouse splenocytes and co-cultured them with overexpressing SEMA6A human lung cancer cell lines. SEMA6A increased the proportion of T-cell and the migration ability of splenocytes. Furthermore, we analyzed the combined effect of SEMA6A and SEMA3A on patient’s survival by Kaplan-Meier survival curves because SEMA6A and SEMA3A were demonstrated to have the same receptors: Plexin A2 and Plexin A4. The data shows that poor survival rate is significant in patients who have low expressions of SEMA6A and high expression of SEMA3A (p<0.01) while the other combinations of SEMA6A and SEMA3A expressions do not significantly influence the survival of patients. Accordingly, we aimed to study the characteristics of SEMA6A on regulation of immunity ex vivo and the interaction of SEMA6A and SEMA3A in immunity. In order to avoid the influence of endogenous SEMA3A, at first, we knocked down the expression of SEMA3A in mouse lung cancer cell, KLN205. Mouse splenocytes were subsequently isolated and co-cultured with different condition of KLN205 and divided into four groups: Control, SEMA6A, SEMA3A, SEMA6A+SEMA3A. After three or nine days of cultivation, we compared the migration, proliferation, cytotoxic activity of splenocytes between the groups and predicted the immune cells that might be regulated by SEMA6A and SEMA3A using ImmQuant and GSEA. The results indicated that SEMA6A could enhance the cell number and migration ability of splenocytes and reduce proliferation of T regulatory cells compared to the control after nine days. Besides, SEMA6A could extenuate the suppressive effect of SEMA3A in proliferation and cytotoxic capability of T cytotoxic cells. The suppressive effect of SEMA3A on cytotoxic activity of natural killer cells was also extenuated by SEMA6A. Finally, we analyzed gene expressions in these splenocytes utlizing microarray. Based on the microarray results, we predicted that SEMA6A could induce the activity of dendritic cells and attenuate the suppressive effect of SEMA3A in B cells using ImmQuant and GSEA software. However, there was no significant effect of SEMA6A on M1 and M2 macrophages. In conclusion, SEMA6A could induce anti-cancer immunity through either directly regulating the signialing pathway of immune cells or reducing the immune inhibition of SEMA3A. Thus, SEMA6A may be a potential target for cancer immunotherapy in the future. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T04:25:52Z (GMT). No. of bitstreams: 1 ntu-107-R05b21023-1.pdf: 4125224 bytes, checksum: cf2585482842d74bb24c68cec6a644fc (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 致謝 I
中文摘要 II ABSTRACT IV 第一章、文獻回顧 1 1-1 肺癌 1 1-1-1 肺癌的基本介紹 1 1-1-2 肺癌的致病機轉 1 1-1-3 肺癌的分期與治療 3 1-2 SEMAPHORIN 4 1-2-1 Semaphorin的介紹 4 1-2-2 Semaphorin主導的訊息傳遞路徑 4 1-2-3 Semaphorin與癌症的研究 5 1-2-4 Semaphorin與免疫之間的關係 6 1-2-5 Semaphorin6A的介紹 6 1-2-6 Semaphorin3A的介紹 7 1-3 免疫治療(IMMUNOTHERAPY) 8 1-3-1 免疫細胞的基本種類與功能 8 1-3-2 免疫治療的基本定義與原理 10 1-3-3 免疫治療主要應用與發展 11 1-3-4 免疫治療目前的限制與未來的趨勢 13 1-4 試驗性研究(PILOT STUDY) 15 第二章、研究動機與架構 16 第三章、實驗材料與方法 17 3-1 培養液配置 (MEDIUM PREPARATION) 17 3-2 細胞培養與繼代 (CELL CULTURE AND SUBCULTURE) 19 3-3 慢病毒包裝系統 (LENTIVIRUS PACKING SYSTEM) 19 3-4 過渡性轉染 (TRANSIENT TRANSFECTION) 21 3-5 病毒感染 (CELL INFECTION) 22 3-6 分析RNA表現 (RNA) 23 3-7 分析蛋白質表現 (WESTERN BLOT ANALYSIS) 24 3-8 聚合酶連鎖反應(POLYMERASE CHAIN REACTION,PCR) 26 3-9 蛋白質純化系統(PROTEIN PURIFICATION) 28 3-10 小鼠脾臟細胞製備(PREPARATION OF MOUSE SPLENOCYTES) 29 3-11 免疫細胞的分離(T CELL AND NK CELL ISOLATION) 29 3-12 免疫細胞增生分析(PROLIFERATION ASSAY) 30 3-13 免疫細胞的培養(CULTURE AND STIMULATION) 31 3-14 穿膜試驗(TRANSWELL ASSAY) 31 3-15 流式細胞儀分析(FLOW CYTOMETRIC ANALYSIS) 31 3-16 自然殺手細胞活性試驗(NK CELL CYTOTOXICITY ACTIVITY) 32 3-17 酵素連結免疫吸附法(ENZYME-LINKED IMMUNOSORBENT ASSAY) 33 3-18 以IMMQUANT線上軟體對微陣列數據進行分析。 35 3-19 基因及富集分析(GENE SET ENRICHMENT ANALYSIS, GSEA) 36 3-20 統計方法(STATISTICAL ANALYSIS) 36 第四章、實驗結果 37 4-1分析SEMA6A及SEMA3A在KLN205小鼠肺癌細胞株中的基因表現量 37 4-2探討SEMA6A及SEMA3A對共培養三天之脾臟細胞遷移能力的影響 37 4-3探討SEMA6A及SEMA3A對共培養三天之特定免疫細胞的比例變化 38 4-4探討SEMA6A及SEMA3A在對於整體免疫細胞遷移能力的影響 39 4-5探討SEMA6A及SEMA3A對於全體T淋巴細胞增生能力的影響 39 4-6探討SEMA6A及SEMA3A對毒殺型T細胞的增生能力及毒殺活性 40 4-7探討SEMA6A及SEMA3A對於調節型T細胞的增生能力 41 4-8探討SEMA6A及SEMA3A對於輔助型T淋巴細胞的增生能力及其細胞激素的分泌情形 41 4-9探討SEMA6A及SEMA3A對於自然殺手細胞毒殺活性及其細胞激素的分泌情形 42 4-10利用微陣列分析尋找SEMA6A及SEMA3A可能調控之免疫細胞 43 4-11利用GSEA預測SEMA6A及SEMA3A可能調控之免疫細胞 44 第五章、結論與討論 48 5-1 結論 48 5-2 探討SEMA6A與SEMA3A調控免疫細胞的機制 48 5-3 探討SEMA6A誘導毒殺型T細胞增生所引發的抗癌免疫 49 5-4 探討由SEMA6A誘導自然殺手細胞所引發的抗癌免疫 50 5-5 探討SEMA6A抑制調節型T細胞及其所觸發的免疫反應 50 5-6 探討SEMA6A對於輔助型T細胞之間的調控關係 51 5-7 探討由SEMA6A誘導樹突細胞所引發的抗癌免疫 52 5-8 探討由SEMA6A誘導B細胞所引發的抗癌免疫 53 5-9 探討SEMA6A在各種免疫細胞之間的調控機制 53 5-10 探討SEMA6A及SEMA3A藉由INTERLEUKIN-2 (IL-2)所刺激免疫細胞的增生 54 5-11 比較毒殺型T細胞與輔助型T細胞的增生效果差異 56 5-12 探討腫瘤細胞與SEMA3A的表現量之間的關係 56 5-13 探討SEMA6A對免疫細胞遷移能力以及在生物體中所代表的意義 57 第六章、未來研究方向 59 參考文獻 96 | |
dc.language.iso | zh-TW | |
dc.title | Semaphorin 6A在非小細胞肺癌細胞株中所造成的免疫刺激效果及機制之研究 | zh_TW |
dc.title | Effect and Mechanism of Semaphorin 6A on Immune Stimulation in Non Small Lung Cancer Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 蔡孟勳(Mong-Hsun Tsai) | |
dc.contributor.oralexamcommittee | 賴亮全(Liang-Chuan Lai),李心予(Hsin-Yu Lee) | |
dc.subject.keyword | 肺癌,Semaphorin 6A,Semaphorin 3A,毒殺型T細胞,調節型T細胞,自然殺手細胞,細胞性免疫,抗癌免疫, | zh_TW |
dc.subject.keyword | lung cancer,Semaphorin 6A,Semaphorin 3A,cytotoxic T cells,regulatory T cells,natural killer cells,cellular immunity,anti-cancer immunity, | en |
dc.relation.page | 104 | |
dc.identifier.doi | 10.6342/NTU201704447 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-08-15 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生命科學系 | zh_TW |
顯示於系所單位: | 生命科學系 |
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