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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃麗華 | |
| dc.contributor.author | Hao-Tien Wang | en |
| dc.contributor.author | 王皓恬 | zh_TW |
| dc.date.accessioned | 2021-06-17T00:24:32Z | - |
| dc.date.available | 2022-12-31 | |
| dc.date.copyright | 2012-09-19 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-05-04 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66177 | - |
| dc.description.abstract | 免疫療法不只能有效地對抗腫瘤，其所產生的免疫記憶也能提供一個長時間的保護，避免腫瘤復發。然而，免疫療法所刺激活化的免疫細胞，往往因為腫瘤內不同機制的存在，無法正常發揮清除腫瘤的作用，影響治療效果。在本篇研究中，我們嘗試利用兩種不同的方式，來增強免疫療法(granulocyte macrophage colony-stimulating factor + interleukin-12)的療效。Calreticulin (CRT)是一個存在於內質網(endoplasmic reticulum)中的輔助蛋白(chaperon)，已被證實具有抗血管新生並抑制腫瘤生長的功能。在第一部份的實驗中，我們發現CRT 能增加腫瘤內皮細胞上黏附分子(adhesion molecule)的表現，這將有助於淋巴細胞與內皮細胞的結合，並增加淋巴細胞的穿透。因此，CRT能藉由增加淋巴細胞穿透至腫瘤的數量，有效提升免疫療法的抗腫瘤功效。另一方面，我們也嘗試著將免疫療法與endostatin (ED)和pigment epithelium-derived factor (PEDF)作結合。我們發現，相較於治療小腫瘤，免疫療法在治療大腫瘤時的療效會明顯減弱許多，而ED及PEDF的參與，將能增加對大腫瘤的抑制效果。進一步藉由觀察治療後不同時間點腫瘤內的變化，我們發現 ED 與 PEDF 可降低大腫瘤中的抑制免疫反應，使免疫療法在其中更易發揮治療效果。因此，縱使參與的機制不盡相同，我們所使用的兩種抗血管新生治療法，都能幫助經由免疫療法所刺激的免疫細胞，更有效率地在腫瘤處發揮其毒殺的功能，也因此，提升了免疫療法的治療效果。 | zh_TW |
| dc.description.abstract | Immunotherapy is an approach to systemically eradicate tumors, and the immunological memory established further provides long-term protection from cancer recurrence. However, the tumor-specific effector cells elicited by immunotherapy are usually inhibited by multiple mechanisms existing in the tumor microenvironment, thus greatly reducing the therapeutic efficacy. Here, we have attempted to improve immunotherapy (granulocyte macrophage colony-stimulating factor + interleukin-12) using various approaches. Calreticulin (CRT), a chaperon residing in the endoplasmic reticulum, has been shown to exert anti-angiogenic activity and inhibit tumor growth. In the first part of this study, we demonstrated a novel role for CRT, which can up-regulate the expression of adhesion molecules on tumor endothelial cells, resulting in enhanced lymphocyte-endothelial cell interactions and subsequent lymphocyte infiltration. Thus, combining CRT with immunotherapy would improve the anti-tumor effects of immunotherapy by markedly increasing the levels of tumor-infiltrating lymphocytes. We also examined the effect of combining immunotherapy with endostatin (ED) and pigment epithelium-derived factor (PEDF). While immunotherapy alone was much less effective in treating large tumors than in treating small tumors, ED and PEDF helped to improve the anti-tumor effect of immunotherapy. Observations from the dynamic changes in the tumor microenvironment revealed that ED + PEDF can alleviate immunosuppression, which might be related to reduce VEGF levels, making the tumors more vulnerable to immunotherapy. Therefore, although these two approaches mediate different mechanisms, both of the anti-angiogenic therapies can promote the function of immunotherapy-stimulated effector cells within the tumor region and thus improve the immunotherapeutic effects. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T00:24:32Z (GMT). No. of bitstreams: 1 ntu-101-D95445009-1.pdf: 12963564 bytes, checksum: 6ca2e7e90a0618e919161e5e6c57fe38 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 中文摘要…………………………………………………………………….......... ⅰ
Abstract………………………………………………………….......................... ⅱ Abbreviations…………………………………………………………………… ⅳ Table of Contents………………………………………………………............ ⅵ Chapter 1 Introduction.................................................................................. 1 1 Hepatocellular Carcinoma………………………………………………. 2 1.1 Tumor cell alterations ………………………………………………… 2 1.2 Angiogenesis………………………………………………………….. 3 1.3 Immunosuppression…………………………………………………... 4 1.4 Endothelial cell anergy………………………………………………... 5 2 Anti-angiogenic therapy………………………………………………….. 6 2.1 Anti-immunosuppression……………………………………………... 7 2.2 Reversion of endothelial cell anergy………………………………….. 8 2.3 Combination of anti-angiogenic therapies……………………………. 9 2.4 Calreticulin……………………………………………………………. 9 2.4.1 Functional domains of CRT……………………………………. 10 2.4.2 Non-ER functions of CRT……………………………………… 12 2.5 Endostatin……………………………………………………………... 14 2.5.1 The anti-tumor activity of ED………………………………….. 14 2.5.2 Mechanistic studies of ED……………………………………... 15 2.6 Pigment epithelium-derived factor……………………………………. 16 2.6.1 Direct anti-tumor effects of PEDF……………………………... 17 2.6.2 Indirect anti-tumor effects of PEDF……………………………. 18 2.6.3 Mechanistic studies of PEDF…………………………………... 18 3 Immunotherapy…………………………………………………………... 20 3.1 Granulocyte macrophage colony-stimulating factor………………….. 20 3.2 Interleukin-12…………………………………………………………. 21 4 Viral vector………………………………………………………………... 22 4.1 Sindbis virus…………………………………………………………... 22 4.2 Sindbis virus as an expression vector…………………………………. 23 4.3 Adenovirus……………………………………………………………. 24 4.4 Adenovirus as an expression vector…………………………………... 24 5 Specific aims……..………………………………………………………... 25 5.1 To explore the role of CRT in promoting immunotherapy……………. 26 5.2 To employ anti-angiogenic therapy to diminish immunosuppression... 26 Chapter 2 Materials and Methods……………………………………….. 28 1 Materials…………………………………………………………………... 29 1.1 Cell culture medium…………………………………………………... 29 1.2 Cell line and primary cell……………………………………………... 29 1.3 Buffer solution………………………………………………………… 30 1.4 Primer…………………………………………………………………. 31 2 Methods……………………………………………………………………. 32 2.1 Isolation and culture of HUVEC……………………………………… 32 2.2 Generation of recombinant sindbis viral vector or adenoviral vector… 32 2.2.1 Construction of recombinant Sindbis viruses expressing EGFP, CRT or the cluster II region of LRP…………………... 32 2.2.2 Production of recombinant sindbis viruses…………………… 33 2.2.3 Construction of recombinant adenoviral vectors expressing EGFP, ED, PEDF, GM-CSF, or IL-12………………………... 34 2.2.4 Production of recombinant adenoviruses……………………... 34 2.2.5 Titration of adenoviruses……………………………………... 35 2.3 Purification of recombinant CRT protein (rCRT)...…………………... 36 2.4 Virus-mediated gene expression in vitro……………………………… 36 2.5 Coomassie blue staining and western blot analysis…………………... 37 2.6 Recombinant CRT up-regulates adhesion molecule expression……… 39 2.7 Leukocyte- or lymphocyte-endothelial cell adhesion assay…………... 39 2.8 Fractionation of nuclear or cytoplasmic proteins……………………... 40 2.9 Animal experiments…………………………………………………... 41 2.9.1 Generation of orthotopic liver tumors………………………... 41 2.9.2 Evaluation of Sb/CRT-mediated therapeutic efficacy………… 42 2.9.3 Evaluating the therapeutic efficacy of 4-in-1 treatment……… 43 2.10 Tissue staining……………………………………………………….. 44 2.10.1 Immunohistochemical staining…………………………….... 44 2.10.2 Immunofluorescence staining……………………………….. 46 2.10.3 TUNEL assay………………………………………………... 47 2.11 Flow cytometric analysis…………………………………………….. 47 2.12 Quantitative reverse transcription-PCR (qRT-PCR) analysis of immunomodulatory gene expression……………………………….. 48 2.13 Statistical analysis…………………………………………………… 49 Chapter 3 Results…………………………………………………………… 50 1.1 A novel role of CRT…………………………………………………... 51 1.1.1 Up-regulation of adhesion molecules on HUVECs…...……… 51 1.1.2 CRT-induced up-regulation of adhesion molecules occurs via NF-κB activity………………………………………………... 52 1.1.3 A temporal difference between the induction effect and anti-angiogenic function……………………………………… 53 1.2 The effects of CRT on the tumor microenvironment…………………. 54 1.2.1 CRT functions systemically to inhibit the growth of distant orthotopic liver tumors……………………………………….. 54 1.2.2 CRT up-regulates ICAM-1 expression on tumor endothelial cells…………………………………………………………… 56 1.2.3 CRT treatment increases lymphocyte infiltration in tumors….. 57 1.3 CRT potentiates the anti-tumor activity of immunotherapy by increasing tumor-infiltrating lymphocytes…………………………… 57 1.3.1 The improvement of immunotherapy by CRT is associated with up-regulation of adhesion molecules...………………….. 58 1.3.2 CRT treatment facilitates immunotherapy-stimulated lymphocyte infiltration into the tumor region………………… 59 1.3.3 CRT treatment reduces immunosuppression in the tumor environment to facilitate immunotherapy…………………….. 61 2.1 Combination of ED and PEDF………….…………………………….. 63 2.1.1 Ad/ED and Ad/PEDF result in synergistic anti-tumor effects... 63 2.2 Combination of anti-angiogenic therapy with immunotherapy………. 64 2.2.1 Combination of anti-angiogenic therapy with immunotherapy synergistically represses large liver tumors…………………... 65 2.2.2 4-in-1 strategy increases tumor apoptosis and lymphocyte Infiltration…………………………………………………….. 66 2.3 Mechanisms to impede immunotherapeutic efficacy………………… 67 2.3.1 Large tumors present more exacerbated immunosuppression than small tumors……………………………………………... 68 2.3.2 Anti-angiogenic therapy diminishes immunosuppression in the tumor microenvironment…………………………………. 69 2.4 Ad-mediated immunotherapy exerted systemic and memory effects against the original tumors…………………………………………….. 71 Chapter 4 Discussion and Conclusion………………………………….. 73 1 Anti-angiogenic therapy acts to enhance immunotherapy……………... 74 2 Remarks on the CRT therapy……………………………………………. 78 2.1 The effects on endothelial cells……………………………………….. 78 2.2 Choice of the sindbis viral vector to deliver the CRT gene…………… 80 2.3 The influence on injected muscle……………………………………... 81 2.4 Different anti-tumor mechanism from phagocytosis role……..……… 82 3 Remarks on the 4-in-1 therapy…..………………………………………. 82 3.1 Anti-angiogenic therapy is inadequate to treat large tumors…...……... 82 3.2 Immunosuppression in large tumors obstructs immunotherapy……… 83 4 Conclusion………………………………………………………………… 85 Chapter 5 Figures…………………………………………………………... 88 Figure 1. Purification of recombinant CRT protein……………………………. 89 Figure 2. Recombinant CRT protein up-regulates adhesion molecule expression……………………………………………………………. 90 Figure 3. rCRT protein enhances leukocyte- and lymphocyte-endothelial cell interactions………………………………………………………….... 91 Figure 4. The CRT-induced expression of adhesion molecules on HUVECs is NF-κB-dependent……………………………………………………. 92 Figure 5. Kinetics of the surface expression of adhesion molecules and HUVEC viability…………………………………………………….. 93 Figure 6. Intramuscular CRT treatment inhibits orthotopic liver tumor growth.. 94 Figure 7. CRT systemically inhibits liver tumor growth………………………. 95 Figure 8. Intramuscular CRT treatment enhances the expression of adhesion molecules by tumor endothelial cells...……………………………… 96 Figure 9. The effects of intramuscular CRT treatment on the expression of adhesion molecules in different tissues……………………………… 97 Figure 10. CRT treatment reduces the number of blood vessels and increases lymphocyte infiltration into tumors………………………………… 98 Figure 11. The effects of intramuscular CRT treatment on lymphocyte infiltration in different tissues…………………………………….. 99 Figure 12. CRT potentiates the efficacy of immunotherapy by increasing ICAM-1 expression……………………………………………….. 100 Figure 13. Combining CRT with immunotherapy significantly increases ICAM-1 expression on tumor endothelial (CD31+) cells…………. 101 Figure 14. CRT potentiates the efficacy of immunotherapy by enhancing the infiltration of lymphocytes into tumors…………………………... 102 Figure 15. CRT potentiates the efficacy of immunotherapy by enhancing the infiltration of lymphocytes into tumors………………………....... 103 Figure 16. CRT improves the efficacy of immunotherapy by enhancing the infiltration of lymphocytes into DEN-induced multifocal tumors... 104 Figure 17. Kinetics of activated lymphocytes in the tumor microenvironment after the indicated treatments……………………………………... 105 Figure 18. CRT treatment enhances the infiltration of M1 macrophages into tumors……………………………………………………………... 106 Figure 19. CRT/GM + IL-12 combined therapy reduces the relative levels of immunosuppressive molecules and increases the levels of IFN-γ.. 107 Figure 20. CRT/GM + IL-12 combined therapy ameliorates tumor immunosuppression………………………………………………. 108 Figure 21. Synergistic anti-tumor effects induced by combining two anti-angiogenic factors……………………………………………. 109 Figure 22. In vitro expression of Ad/ED and Ad/PEDF……………………… 110 Figure 23. Synergistic anti-tumor effects of the 4-in-1 strategy on large Tumors…………………………………………………………….. 111 Figure 24. Immunohistochemical staining to determine the mechanisms associated with the anti-tumor effects of various treatments……... 112 Figure 25. Representative photographs of IHC staining……………………... 113 Figure 26. Higher intratumoral expression of immunosuppressive molecules in large tumors than in small tumors……………………………… 114 Figure 27. Increased levels of immunosuppressive molecules are present in large tumors treated with immunotherapy alone………………….. 115 Figure 28. The 4-in-1 strategy enhances the anti-tumor effects by reducing immunosuppression in the tumor region………………………….. 116 Figure 29. The 4-in-1 strategy reduces immunosuppression and increased effectors in the tumor region……………………………………… 117 Figure 30. Ad-mediated immunotherapy exerts systemic and memory effects against the original tumors………………………...……………… 118 Figure 31. The 4-in-1 strategy reduces the levels of MDSCs………………... 119 Figure 32. CRT treatment enhances cell apoptosis…………………………… 120 Chapter 6 References……………………………………………………... 121 Appendix……………………………………………………………………….. 134 | |
| dc.language.iso | en | |
| dc.subject | 免疫療法 | zh_TW |
| dc.subject | 抗血管新生 | zh_TW |
| dc.subject | 基因治療 | zh_TW |
| dc.subject | gene therapy | en |
| dc.subject | immunotherapy | en |
| dc.subject | anti-angiogenic therapy | en |
| dc.title | 抗血管新生之基因治療可增進原位肝腫瘤之免疫療法的療效 | zh_TW |
| dc.title | Anti-angiogenic Gene Therapies Enhance the Effects of Immunotherapy in Orthotopic Liver Tumors | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 賈景山,李建國,李財坤,江伯倫 | |
| dc.subject.keyword | 抗血管新生,基因治療,免疫療法, | zh_TW |
| dc.subject.keyword | anti-angiogenic therapy,gene therapy,immunotherapy, | en |
| dc.relation.page | 136 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-05-07 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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