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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 周涵怡 | zh_TW |
| dc.contributor.advisor | HAN-YI E. CHOU | en |
| dc.contributor.author | 蘇暄潔 | zh_TW |
| dc.contributor.author | Xuan-Jie Su | en |
| dc.date.accessioned | 2024-08-26T16:26:04Z | - |
| dc.date.available | 2024-08-27 | - |
| dc.date.copyright | 2024-08-26 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-09 | - |
| dc.identifier.citation | 1. Cheng, F.-C., et al., Morbidity and mortality of oral cancer in Taiwan: Trends from 2000 to 2021. Journal of Dental Sciences, 2023. 18(3): p. 1338-1346.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95048 | - |
| dc.description.abstract | 口腔癌是全球常見的癌症之一，由於病變部位容易轉移到淋巴結，導致患者 預後不良，五年存活率極低。實驗室先前研究顯示，口腔癌微環境的酸化與腫瘤轉 移密切相關。腫瘤微環境通過不同因子影響腫瘤轉移及免疫系統，其中胞外體作為 生物體內訊息傳遞的工具，參與腫瘤和免疫調節之間的交互作用。然而，目前對酸 化微環境中胞外體對 T 細胞的影響尚未充分了解。
本研究旨在探討酸化微環境中之口腔癌細胞所釋放的胞外體對免疫 T 細胞 的影響。我們使用蛋白質體學和轉錄體學技術分析口腔癌細胞在酸化環境中釋放 的胞外體載物，並將胞外體添加至 T 細胞進行刺激，觀察 T 細胞活性是否受到影 響，並測試 T 細胞的毒殺功能。實驗結果顯示，酸化微環境會導致口腔癌細胞釋 放出含有不同蛋白質和 miRNA 的胞外體，這些胞外體能夠誘導 T 細胞向耗竭狀態 發展，削弱其免疫毒殺功能。這些發現揭示了口腔癌酸化微環境中的胞外體在免疫 調節中的重要作用，並提示酸化微環境可能是口腔癌免疫治療的一大障礙。 這些研究結果有助於更好地理解酸化微環境對口腔癌免疫治療的影響，並 為改進免疫治療策略提供新的思路。我們希望能夠利用這些發現，進一步評估和優 化口腔癌患者的免疫治療方案，最終改善患者的臨床預後。 | zh_TW |
| dc.description.abstract | Oral cancer is a very prevalent cancer worldwide, particularly prone to metastasizing to lymph nodes, and a low five-year survival rate. Previously our laboratory studies have indicated that acidosis of the oral cancer microenvironment is closely associated with tumor metastasis. The tumor microenvironment influences tumor metastasis and the immune system through various factors, among which EVs serve as crucial mediators of intercellular communication, participating in the interplay between tumors and immune regulation. However, the impact of EVs in an acidified microenvironment on T cells in oral cancer remains insufficiently understood.
This study aims to investigate the effects of an EVs derived from acidotic oral cancer cells on the cancer cytotoxicity of immune T cell. We employ proteomics and transcriptomics techniques to analyze the contents of EVs released by acidotic oral cancer cells. Furthermore, we stimulate T cells by adding these EVs to the T cell culture and assess their impact using enzyme-linked immunosorbent assay (ELISA) and proteomics. Additionally, microscopy time lapse acquisitions is utilized to evaluate the cytotoxic function of T cells. Experimental results have shown that an acidotic microenvironment induces oral cancer cells to release EVs containing distinct proteins and miRNAs, which can drive T cells towards an exhausted state, thereby impairing their cancer cytotoxic function. These findings reveal the significant role of EVs in one cover immune regulation and suggest that an acidotic microenvironment could be a major barrier to effective immunotherapy for oral cancer. These research outcomes contribute to a better understanding of the impact of an acidified microenvironment on oral cancer immunotherapy and provide new insights for improving immunotherapeutic strategies. We hope to leverage these findings to further evaluate and optimize immunotherapy regimens for oral cancer patients, ultimately enhancing their clinical prognosis. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-26T16:26:04Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-26T16:26:04Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 致謝 I
中文摘要 II ABSTRACT III CONTENTS V LIST OF FIGURES VIII CHAPTER 1 INTRODUCTION - 1 - 1.1 Oral cancer - 1 - 1.2 Tumor microenvironment acidosis - 1 - 1.3 Extracellular vesicles - 2 - 1.4 The impact of acidic tumor microenvironment on T cell exhaustion and tumor progression - 2 - 1.5 Treatment modalities for oral cancer - 3 - 1.6 Immunotherapy - 4 - 1.7 Hypothesis - 5 - 1.8 Experimental design - 5 - CHAPTER 2 MATERIAL AND METHODS - 6 - 2.1. Oral squamous cell carcinoma cell culture - 6 - 2.2. Isolation of PBMCs from whole blood - 6 - 2.3 In vitro T cell exhaustion - 7 - 2.4 Extracellular vesicles solation - 7 - 2.4.1 Tangential Flow Filtration (TFF) - 7 - 2.5 Characteristics of extracellular vesicles - 8 - 2.5.1 Nanoparticles Tracking Analysis (NTA) - 8 - 2.5.2 Transmission Electron Microscope (TEM) - 8 - 2.5.3 Proteomics analysis - 9 - 2.5.4 miRNA extraction, RNA library construction and sequencing - 11 - 2.5.5 microRNA-seq data analysis - 11 - 2.6 T cell functional assay - 12 - 2.6.1 Extracellular vesicles labeling - 12 - 2.6.2 Cytokine assays - 13 - 2.6.3 Proteomic analysis - 13 - 2.6.4 Label-free live cell imaging - 14 - 2.7 Statistical analysis - 15 - CHAPTER 3 RESULTS - 16 - 3.1 Acidosis of tumor microenvironment and extracellular vesicle collection. - 16 - 3.2 Collection and characterization of SAS EVs by tangential flow filtration - 16 - 3.3 Acidosis affects on the protein composition of SAS EVs. - 17 - 3.4 Regulation of immune system and T cell exhaustion through acidified EVs loaded with miRNA - 19 - 3.5 Establishment of a chronic induction model of T cell exhaustion by EV released from oral cancer cells - 21 - 3.6 Impact of different pH values on SAS release and its effect on T cell function. - 22 - 3.7 EVs released by oral cancer cells impact the proteome of chronically stimulated T cells. - 24 - CHAPTER 4 CONCLUSION AND DISCUSSION - 29 - REFERENCE - 31 - LIST OF FIGURES Figure 1. Cell culture and collection of EVs from SAS Cells. - 36 - Figure 2. Collection and characteristics of SAS-derived EVs isolated by TFF. - 37 - Figure 3. Acidosis induces SAS to release the EVs analysis with GSEA. - 38 - Figure 4. Differential expression of proteins in EVs proteomics analysis - 39 - Figure 5. Proteomic Gene Set Enrichment Analysis (GSEA) of EVs. - 40 - Figure 6. Differential miRNA expression is observed under induction at pH 7.4 and pH 6.6. - 42 - Figure 7. miRNAs involved in immune regulation. - 43 - Figure 8. A long-term T cell exhaustion model was established by stimulating T cells with EVs released by oral cancer cells. - 44 - Figure 9. The morphology of T cells stimulated by EVs. - 45 - Figure 10. PKH-labeled EVs were observed to aggregate within T cells. - 46 - Figure 11. Co-culture Live T cell assay with T cells and SAS cells. - 47 - Figure 12. Continuous imaging analysis data of LIVE T cell assay with EVE Analytic images captured sequentially. - 48 - Figure 13. Exhaustion Trend in T Cells Stimulated by EVs - 49 - Figure 14. Stimulation of T cells with EVs at varying pH levels results in differential protein expression profiles. - 50 - Figure 15. Related with T cell exhaustion proteins. - 51 - Figure 16. Gene Set Enrichment Analysis (GSEA) of T cell proteomics. - 53 - Figure 17. Upregulation of LARP7 and ARID1A Proteins in pH 6.6 Group. - 54 - | - |
| dc.language.iso | en | - |
| dc.subject | 酸化微環境 | zh_TW |
| dc.subject | 口腔癌 | zh_TW |
| dc.subject | T細胞耗竭 | zh_TW |
| dc.subject | T細胞 | zh_TW |
| dc.subject | 胞外體 | zh_TW |
| dc.subject | extracellular vesicles | en |
| dc.subject | T cell | en |
| dc.subject | T cell exhaustion | en |
| dc.subject | oral cancer | en |
| dc.subject | acidotic microenvironment | en |
| dc.title | 酸化口腔癌之胞外體對免疫 T 細胞的影響 | zh_TW |
| dc.title | Effects of Extracellular Vesicles from Acidotic Oral Cancer on Immune T Cells. | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 鄭世榮;沈湯龍;饒梓明 | zh_TW |
| dc.contributor.oralexamcommittee | SHIH-JUNG CHENG;Tang-Long Shen;Tzu-Ming Jao | en |
| dc.subject.keyword | 口腔癌,酸化微環境,胞外體,T細胞,T細胞耗竭, | zh_TW |
| dc.subject.keyword | acidotic microenvironment,oral cancer,extracellular vesicles,T cell,T cell exhaustion, | en |
| dc.relation.page | 54 | - |
| dc.identifier.doi | 10.6342/NTU202404061 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-08-10 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 口腔生物科學研究所 | - |
| 顯示於系所單位： | 口腔生物科學研究所 | |
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