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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 楊宏志 | zh_TW |
dc.contributor.advisor | Hung-Chih Yang | en |
dc.contributor.author | 林家安 | zh_TW |
dc.contributor.author | Chia-An Lin | en |
dc.date.accessioned | 2023-09-24T16:12:01Z | - |
dc.date.available | 2023-11-09 | - |
dc.date.copyright | 2023-09-23 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-08-10 | - |
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Blood, The Journal of the American Society of Hematology, 118(3), 499-509. 54. Johnson, L. A., Morgan, R. A., Dudley, M. E., Cassard, L., Yang, J. C., Hughes, M. S., ... & Rosenberg, S. A. (2009). Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood, The Journal of the American Society of Hematology, 114(3), 535-546. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90249 | - |
dc.description.abstract | T細胞受體工程性T細胞 (engineered TCR-T cell)是一種應用於過繼性T細胞療法(adoptive T-cell therapy)的改造T細胞,對於治療人類癌症具有巨大的潛力。將患者周邊血中分離出自體CD8+ T細胞,在體外將細胞進行培養放大後,透過基因編輯讓細胞表達對腫瘤具有特異性的T細胞受體,最後再重新輸注回患者體內,以更有效率地清除腫瘤細胞。為了提升治療效率,測量這些T細胞受體工程性T細胞之效用功能的好壞至關重要。而其中,T細胞受體的功能親和力 (functional avidity)就是決定T細胞功能的關鍵因素之一,它反映了T細胞對不同濃度的抗原之反應能力。因此,為了能夠有效地評估T細胞受體的功能親和力,我們利用缺乏內源性T細胞受體的Jurkat細胞株開發了一個雙參數報告系統 (dual-parameter reporter system)。 這個系統能夠藉由報告基因的表達,分析在T 細胞活化中十分重要的轉錄因子NFAT和NF-κB的活性,來測量T細胞活化的程度。通過將具有腫瘤特異性的TCR轉導到這些報告細胞中,我們可以在較繁雜的T細胞功能測試前,就先快速地篩選出具有高功能親和力的候選T細胞受體。此外,由於此系統能夠同時測量NFAT和NF-κB的活性,相較於評估單一的T細胞活化路徑,更能夠提高功能親和力的可靠性和參考價值,並且可以深入比較兩個路徑與T細胞功能之間的關聯性。這個報告系統能夠加速用於癌症治療的T細胞受體工程性T細胞的篩選。透過測量候選T細胞受體的功能親和力,我們可以優先篩選出可能具有理想之效用功能的T細胞受體工程性T細胞,以此提高免疫細胞療法的效率。 | zh_TW |
dc.description.abstract | T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising approach for adoptive T cell immunotherapy (ACT) and hold great potential in the treatment of human cancer. Autologous CD8+ T cells can be isolated from patients' peripheral blood, expanded in vitro, modified to express tumor-specific TCRs, and finally reinfused into patients’ body to improve antitumor ability. To optimize this treatment strategy, it is crucial to evaluate the efficacy of T cell effector functions. One key factor in determining T cell functionality is the functional avidity of the TCR, which reflects the T cell's response to varying antigen levels. To efficiently assess TCR functional avidity, we have developed a dual parameter reporter system utilizing the Jurkat cell line devoid of endogenous TCRs. This system allows for the analysis of NFAT and NF-κB activities, two critical transcription factors required for T cell activation. By transducing tumor-specific TCRs into these reporter cells, we can effectively select TCR candidates with enhanced effector functions before conducting functional assays on tumor-specific TCR-T cells. Additionally, the system enables simultaneous measurement of the expression levels of NFAT and NF-κB, enhancing the reliability and reference value of the measured functional avidity. Furthermore, it enables a comparative analysis of the two TCR activation signaling pathways and the effector functions of engineered TCR-T cells, providing valuable insights into their interplay. Ultimately, this system holds the potential to expedite the development of effective T cell-based immunotherapies for cancer treatment. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-24T16:12:01Z No. of bitstreams: 0 | en |
dc.description.provenance | Made available in DSpace on 2023-09-24T16:12:01Z (GMT). No. of bitstreams: 0 | en |
dc.description.tableofcontents | 口試委員會審定書 ii
致謝 iii 摘要 iv Abstract v Content 1 1 Introduction 3 1.1 T cell-based immunotherapy in cancer 3 1.1.1 Adoptive cell therapy (ACT) 3 1.1.2 Distinctive features of TCR-T cell compared to CAR-T cell therapy 3 1.1.3 Clinical application of engineered TCR T-cell therapy 5 1.2 The overview of T cell antigen recognition and activation 5 1.3 Optimization of engineered TCR T-cell therapy 7 1.3.1 TCR affinity, avidity, and functional avidity 7 1.3.2 Unexpected downsides of high-affinity TCRs 7 1.3.3 Efficient and precise evaluation of TCR functional avidity 8 2 Specific Aims 10 3 Materials and methods 11 3.1 Plasmid construction 11 3.2 Cell lines and culture conditions 11 3.3 Lentiviral transduction of Jurkat cells 12 3.4 Stimulation experiments and reporter assays 13 3.5 Establishment of the dual parameter reporter Jurkat cell line 14 4 Results 15 4.1 The expression of NFAT reporter of TCR knockout Jurkat cells by different stimulation strategies 15 4.2 Establishment of the dual-parameter reporter Jurkat cells 16 4.2.1 Screening of the reporter Jurkat cells with low-background and high-inducibility of NF-κB expression 16 4.2.2 Troubleshooting for the unexpected cell death caused by PMA and ionomycin stimulation 17 4.2.3 Optimal selection of the ideal clone of the established dual-parameter reporter Jurkat cells 18 5 Discussion 20 5.1 Advantages and limitations of utilizing TCR-KO Jurkat cells to create reporter systems 20 5.2 The importance of NFAT and NF-κB dual-parameter reporter system 21 5.3 The application and future potential of the dual-parameter reporter system in TCR-T cell immunotherapy. 23 6 Figures 24 Figure 1. Stimulation responses of TCR KO and non-KO Jurkat cells. 24 Figure 2. Isolation of transduced reporter Jurkat cells with low background expression and high inducibility of NF-κB. 27 Figure 3. Experimental adjustments to improve cell viability in the screening process of reporter cells. 28 Figure. 4 Selection of the ideal clone from the established dual-parameter reporter Jurkat cells. 30 7 References 32 | - |
dc.language.iso | en | - |
dc.title | 建立雙參數報告系統以有效篩選高功能性T細胞受體以應用於T細胞免疫療法 | zh_TW |
dc.title | Development of a dual-parameter reporter system to facilitate the screening of highly functional T cell receptors for T cell-based immunotherapy | en |
dc.type | Thesis | - |
dc.date.schoolyear | 111-2 | - |
dc.description.degree | 碩士 | - |
dc.contributor.oralexamcommittee | 曾岱宗;董馨蓮 | zh_TW |
dc.contributor.oralexamcommittee | Tai-Chung Tseng;Shin-Lian Doong | en |
dc.subject.keyword | T細胞受體,工程性T細胞,功能親和力,T細胞活化,免疫細胞療法, | zh_TW |
dc.subject.keyword | T cell receptor,engineered T cells,functional avidity,T cell activation,adoptive cell therapy, | en |
dc.relation.page | 37 | - |
dc.identifier.doi | 10.6342/NTU202303793 | - |
dc.rights.note | 同意授權(全球公開) | - |
dc.date.accepted | 2023-08-10 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 微生物學研究所 | - |
顯示於系所單位: | 微生物學科所 |
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