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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73303完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄭文芳(Wen-Fang Cheng) | |
| dc.contributor.author | Nai-Yun Sun | en |
| dc.contributor.author | 孫乃云 | zh_TW |
| dc.date.accessioned | 2021-06-17T07:27:23Z | - |
| dc.date.available | 2024-08-26 | |
| dc.date.copyright | 2019-08-26 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-06-24 | |
| dc.identifier.citation | 1.A. Rotte, J.Y. Jin, V. Lemaire, Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy, Ann Oncol, 29 (2018) 71-83.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73303 | - |
| dc.description.abstract | 本論文旨在研究抗原特異DNA疫苗合併阻斷PD-1或CTLA-4免疫檢查點之抗癌效果及其可能的作用機轉。利用帶有人類乳突病毒16型E6和E7抗原之鼷鼠同種腫瘤移植模式，探討anti-CTLA-4或anti-PD-1抗體是否會增強結締組織生長因子結合E7的嵌合DNA疫苗所誘發之抗原特異的抗癌效果及免疫反應以及可能的機轉。首先，anti-PD-1或anti-CTLA-4抗體合併E7抗原特異DNA疫苗的治療方式相較於單獨使用E7抗原特異之DNA疫苗治療，可以增加鼷鼠體內更強之anti-E7抗體、E7抗原特異之細胞毒性CD8 T淋巴球的數目及其細胞毒殺活性等抗原特異免疫力，以及抗癌效果。此外，在anti-PD-1或anti-CTLA-4抗體合併E7抗原特異DNA疫苗的治療下，鼷鼠體內全身性及腫瘤內的調節性T細胞數目都較單獨使用DNA疫苗的治療更低。更進一步的研究顯示anti-PD-1或anti-CTLA-4抗體合併E7抗原特異DNA疫苗的治療下，鼷鼠腫瘤內的樹突細胞之成熟狀態及其活化E7抗原特異之細胞毒性CD8 T細胞的能力都較單獨使用DNA疫苗的治療更強。總而言之，阻斷免疫檢查點的治療方式可以藉由克服腫瘤微環境內的免疫抑制狀態，以達到增強抗原特異DNA疫苗的抗原特異性之抗腫瘤免疫反應及抗癌效果。抗原特異性的免疫治療合併免疫檢查點的阻斷可以在臨床癌症治療上提供嶄新的治療策略。 | zh_TW |
| dc.description.abstract | I determined the antitumor effects and possible mechanisms of an antigen-specific DNA vaccine combined with PD-1 or CTLA-4 blockade. Using the HPV16 E6/E7+ syngeneic mouse tumor model, we investigated whether anti-CTLA-4 antibody (Ab) or anti-PD-1 Ab increases the antigen-specific antitumor effects and immune response induced by CTGF/E7 chimeric DNA vaccine and the possible mechanisms. Anti-PD-1 Ab or anti-CTLA-4 Ab combined with E7-specific DNA vaccine generated more potent antigen-specific immunity, including anti-E7 Abs and the number and cytotoxic activity of E7-specific cytotoxic CD8+ T lymphocytes, and antitumor effects than E7-specific DNA vaccine alone. In addition, the number of systemic and intratumoral Tregs was lower with the anti-PD-1 or anti-CTLA-4 Ab and E7-specific DNA vaccine. Furthermore, anti-PD-1 and anti-CTLA-4 Abs could enhance the maturation and abilities of intratumoral DCs to activate E7-specific cytotoxic CD8+ T cells. I conclude that immune checkpoint blockade could overcome the immunosuppressive status of the tumor microenvironment to enhance the antigen-specific immunity and antitumor effects generated by an antigen-specific DNA vaccine. Antigen-specific immunotherapy combined with immune checkpoint blockade can be a novel strategy in clinical cancer therapy. | en |
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| dc.description.tableofcontents | 誌謝…………………………………………………………. ………………………......i
中文摘要………………………………………………………………………………...ii Abstract…………………………………………………………………………………iii Contents…………………………………………………………………………………iv List of Figures…………………………………………………………………………...ix Chapter 1: Background Information…………………………………………………......1 1.1. Regulation of Antitumor Immune Responses.....................................................1 1.2. Immune Checkpoint Blockade in Cancer Immunotherapy……………………2 1.3. Antigen-Specific DNA vaccines in Cancer Immunotherapy………………….7 1.4. Aims of the Study…………………………………………………………….10 Chapter 2: Antigen-Specific Antitumor Effects and Immune Responses Induced by DNA Vaccine Combined with Immune Checkpoint Blockade…………………...12 2.1. Introduction…………………………………………………………………..12 2.2. Materials and Methods……………………………………………………….14 2.2.1. Cell lines……………………………………………………………....15 2.2.2. Preparation of DNA vaccine…………………………………………..15 2.2.3. Mice…………………………………………………………………...15 2.2.4. Administration of immune checkpoint inhibitors……………………..16 2.2.5. In vivo tumor treatment………………………………………………..16 2.2.6. Intracellular IFN-γ staining and MHC I-restricted E7 peptide H-2Db tetramer staining analyzed by flow cytometry………………………………17 2.2.7. Isolation of tumor-infiltrating lymphocytes (TILs)…………………...17 2.2.8. Detection of CD4+ T lymphocytes, CD8+ T lymphocytes, IFN-γ-secreting antigen-specific CD8+ cytotoxic T lymphocytes, and antigen-specific CD8+ cytotoxic T lymphocytes from TILs………………...18 2.2.9. In vivo activation markers of tumor-infiltrating CD4+ or CD8+T cells.18 2.2.10. Enzyme-linked immune-absorbent assay (ELISA) for anti-E7 Ab….19 2.2.11. In vitro tumor killing activities………………………………………19 2.2.12. Histology…………………………………………………………….20 2.2.13. Cell staining and flow cytometric analysis…………………………..20 2.2.14. Statistical analysis…………………………………………………...20 2.3. Results……………………………………………………………………..…21 2.3.1. Immune checkpoint blockades enhanced the antitumor effects of E7-specific chimeric DNA vaccine………………………………………….21 2.3.2. Immune checkpoint blockades could also enhance the antitumor effects of MSLN-specific chimeric DNA vaccine…………………………………..22 2.3.3. Immune checkpoint blockades enhanced the antigen-specific CD8+ T cell systemic and local immune responses generated by antigen-specific chimeric DNA vaccine………………………………………………………23 2.3.4. Immune checkpoint blockades could enhance the numbers of antigen-specific CD8+ TILs generated by antigen-specific chimeric DNA vaccine………………………………………………………………………25 2.3.5. DNA vaccine combined with anti-CTLA-4 or anti-PD-1 Abs could enhance the expression of Ki-67 activation marker on the T lymphocytes of TILs……………………………………………………………………….…26 2.3.6. In vitro and ex vivo antigen-specific CD8+ cytotoxic T cells treated with anti-CTLA-4 or anti-PD-1 Ab have enhanced tumor killing activities…...…26 2.3.7. Combination of DNA vaccine with immune checkpoint blockades does not induce significant changes of histopathology and body weight in mice..27 2.3.8. Both PD-1 and CTLA-4 are highly expressed on antigen-specific CD8+ T cells of splenocytes and TILs…………………………………………...…28 Chapter 3: Immune Checkpoint Blockade Combined with the DNA Vaccine Generate More Potent Antitumor T Cell Responses through Suppressing Regulatory T Cells……………………………………………………………..………………...29 3.1. Introduction………………………………………………………………......29 3.2. Materials and Methods……………………………………………………….31 3.2.1. Detection of Tregs and various surface markers of Tregs from splenocytes and TILs………………………………………………………..31 3.2.2. Immunofluorescent staining of Tregs within the tumors……………..32 3.2.3. Statistical analysis…………………………………………………….33 3.3. Results……………………………………………………………………..…33 3.3.1. Combination of DNA vaccine with immune checkpoint blockades decreases the frequencies of Tregs in splenocytes and tumors in mice by reducing CTLA-4 expression of splenocytes and TILs……………………..33 3.3.2. Both PD-1 and CTLA-4 are highly expressed on Tregs of splenocytes and TILs………………………………………………………………......…35 Chapter 4: Immune Checkpoint Blockade Combined with the DNA Vaccine Generate More Potent Antitumor T Cell Responses through Modulating Dendritic Cells……………………………………………………………………………….36 4.1. Introduction………………………………………………………………......36 4.2. Materials and Methods……………………………………………………….37 4.2.1. In vivo maturation status of DCs…………………………………...…37 4.2.2. Activation of antigen-specific CD8+ cytotoxic T cells by DCs from TILs………………………………………………………………………….37 4.2.3. Immunofluorescent staining of DCs within the tumors………………38 4.2.4. Cell staining and flow cytometric analysis…………………………...38 4.2.5. Maturation status of BMM-derived DCs treated with anti-PD-1 or anti-CTLA-4 Ab………………………………………………………..……39 4.2.6. Antigen presenting and processing abilities of the BMM-derived DCs treated with anti-CTLA-4 Ab by flow cytometric analysis………………….40 4.2.7. Statistical analysis…………………………………………………….41 4.3. Results……………………………………………………………………..…41 4.3.1. Anti-CTLA-4 and anti-PD-1 Abs enhance the maturation of DCs in LNs and tumors in vivo…………………………………………………...…41 4.3.2. Anti-CTLA-4 or anti-PD-1 Ab enhances the activation of antigen-specific cytotoxic CD8+ T cells from tumor-infiltrating DCs………42 4.3.3. Higher percentage of immature BMM-derived DCs express PD-1 and PD-L1 than mature BMM-derived DCs…………………………….……….43 4.3.4. Higher percentages of immature DCs express PD-1 and PD-L1 molecules than mature DCs in TILs…………………………………………44 4.3.5. PD-L1 is highly expressed on TC-1 tumor cells……………………...44 4.3.6. Anti-PD-1 Ab enhances the maturation of BMM-derived DCs by upregulating CD80/86 and MHC I molecules………………………………44 4.3.7. Anti-CTLA-4 Ab does not induce the maturation, antigen-processing, and antigen-presenting activities of BMM-derived DCs……………………45 Chapter 5: Discussions…………………………………………………………...…….47 Chapter 6: Conclusions and Future Prospectives……………………………...……….51 Figures………………………………………………………………………………….53 References………………………………………………………………………...........82 Appendices………………………………………………………………………..…..114 | |
| dc.language.iso | en | |
| dc.title | 免疫檢查點阻斷可增強抗原特異DNA疫苗所誘發的抗癌效果及免疫 | zh_TW |
| dc.title | Antitumor Effect and Immunity Generated by Antigen-Specific DNA Vaccine Are Enhanced by Immune Checkpoint Blockade | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 葉坤輝(Kun-Huei Yeh),許駿(Chiun Hsu),何志明(Chih-Ming Ho),劉士任(Shih-Jen Liu) | |
| dc.subject.keyword | 抗原特異DNA疫苗,Anti-PD-1抗體,Anti-CTLA-4抗體,樹突細胞,調節性T細胞, | zh_TW |
| dc.subject.keyword | Antigen-specific DNA vaccine,Anti-PD-1 Ab,Anti-CTLA-4 Ab,Dendritic cell,Regulatory T cell, | en |
| dc.relation.page | 129 | |
| dc.identifier.doi | 10.6342/NTU201900993 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-06-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 腫瘤醫學研究所 | zh_TW |
| 顯示於系所單位： | 腫瘤醫學研究所 | |
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