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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 楊宏志(Hung-Chih Yang) | |
dc.contributor.author | Yi-Hsuan Lin | en |
dc.contributor.author | 林奕萱 | zh_TW |
dc.date.accessioned | 2021-06-16T09:59:20Z | - |
dc.date.available | 2020-08-26 | |
dc.date.copyright | 2020-08-26 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-15 | |
dc.identifier.citation | 1. Ringelhan, M., Pfister, D., O’Connor, T. et al. The immunology of hepatocellular carcinoma. Nat Immunol. 19, 222–232 (2018). 2. Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology. 153(3), 812-826. (2017) 3. Kudo, M. et al. A randomised phase 3 trial of lenvatinib versus sorafenib in firstline treatment of patients with unresectable hepatocellular carcinoma. Lancet. 391, 1163–1173 (2018) 4. Zhu, A. X. et al. Ramucirumab versus placebo as second- line treatment in patients with advanced hepatocellular carcinoma following first- line therapy with sorafenib (REACH): a randomised, double- blind, multicentre, phase 3 trial. Lancet Oncol.16, 859–870 (2015) 5. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol.15(8), 486-499 (2015) 6. Odorizzi PM, Wherry EJ. Inhibitory receptors on lymphocytes: insights from infections. J. Immunol.188, 2957–2965. (2012) 7. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol.10(1), 29-37. (2009) 8. Zheng C, Zheng L, Yoo JK, et al. Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell.169(7), 1342-1356.(2017) 9. Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell.26(5), 605-622.(2014) 10. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol.160, 1224–32.(1998) 11. Nefedova Y, Huang M, Kusmartsev S, Bhattacharya R, Cheng P, Salup R, et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol.172, 464–74. (2004) 12. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+immature myeloid suppressor cells mediate the development of tumor induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res.66, 1123–31.(2006) 13. Cheng AL, Hsu C, Chan SL, Choo SP, Kudo M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol.72(2), 307-319 (2020) 14. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med.212(2),139-148. (2015) 15. Schmittnaegel M, Rigamonti N, Kadioglu E, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med.9(385), eaak9670.(2017) 16. Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell.6,18.(2014) 17. Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 14(2). (2019) 18. Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 109(12), 3993-4002. (2018) 19. Burga RA, Thorn M, Point GR, et al. Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. 64(7), 817-829. (2015) 20. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition. Clin Cancer Res. 23(9):2255-2266. (2017) 21. Macek Jilkova Z, Kurma K, Decaens T. Animal Models of Hepatocellular Carcinoma: The Role of Immune System and Tumor Microenvironment. Cancers (Basel).11(10), 1487 (2019) 22. Zender L, Spector MS, Xue W, et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell.125(7),1253-1267. (2006) 23. Chen X, Calvisi DF. Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am J Pathol.184(4), 912-923. (2014) 24. Liu YT, Tseng TC, Soong RS, et al. A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment. J Immunother Cancer. 6(1), 144. (2018) 25. Huang M, Sun R, Huang Q and Tian Z .Technical Improvement and Application of Hydrodynamic GeneDelivery in Study of Liver Diseases. Front Pharmacol. 8:591. (2017) 26. Chew V, Lai L, Pan L, et al. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc Natl Acad Sci U S A. 114(29). (2017) 27. Bénéchet AP, De Simone G, Di Lucia P, et al. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature. 574(7777), 200-205. (2019) | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60149 | - |
dc.description.abstract | 原發性肝癌是目前全球各種癌症致死率的第二名,而其中肝細胞性肝癌又占了80到90%的原發性肝癌,常見的臨床用藥治療主要是依據巴塞隆納肝癌分級來決定治療方式,依據病人的體能狀態以及腫瘤大小能夠將病人分為初期及末期,由於大部分肝癌病人在確診時通常都已經是接近末期階段,因此在此階段使用的標靶治療是大家共同研究的目標,近年來,合併使用標靶治療以及免疫療法已經成為新興的研究領域,日前美國食藥署即公布,根據臨床試驗第3期結果已核准使用作為肝細胞肝癌的一線用藥,然而其中對於合併治療的機制以及免疫反應尚未清楚。在探討用藥的免疫反應尤其重要的是建立一個理想的小鼠模型來研究其中腫瘤微環境以及免疫細胞的相互作用,因此,我們使用了尾部靜脈高壓注射技術建立了原發性肝癌小鼠模型,並以肝炎病毒的分泌性膜蛋白(HBsAg)作為監測腫瘤生長的標的,接著送入能夠辨認特異性抗原的T細胞來研究在肝癌環境當中的免疫環境,根據結果我們發現在腫瘤初期時送入CD8 T細胞能夠有效清除腫瘤,然而在腫瘤較為後期時,送入T細胞仍無法控制腫瘤,並且造成T細胞衰竭,因此我們希望結合合併藥物治療來加強T細胞的功能並達到清除腫瘤的目標。 | zh_TW |
dc.description.abstract | Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% cases and the prognosis of unresectable HCC (uHCC) is poor. Interestingly, combination immunotherapy with immune-checkpoint inhibitor (ICI) and target therapy has yielded very promising results for treatment of uHCC. Recently, FDA has approved atezolizumab (anti-PDL1) in combination with bevacizumab (anti-VEGF) for the treatment of people with unresectable or metastatic HCC who have not received prior systemic therapy. The immune response and the mechanism of the combinatory remained unknown. Here, we successfully developed a HDI-based spontaneous HCC model to study the antigen-specific T cell response. The HBsAg-HCC model was induced through the HBsAg-Nras-OVAI/II and PTEN-p53/Cas9 plasmids. The expression level of HBsAg could be detected periodically and used to monitor the tumor growth. Our data showed that adoptively transferring naïve CD8 T cells to early-staged tumor could eradicate the tumors. However, the naïve CD8 T cells transferred to late-staged tumors could not control the tumor growth. Additionally, Ag-specific CD8 T cells mostly became liver resident cells and expressed the exhaustion phenotype. The result rendered us the new insight to develop the T cell based therapy combined with target therapy to improve the anti-tumor immunity. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T09:59:20Z (GMT). No. of bitstreams: 1 U0001-1308202013280000.pdf: 2899504 bytes, checksum: 624588b97caaca6d538128c937c48a44 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 致謝 1 摘要 3 Abstract 4 1. Introduction 5 1.1 Hepatocellular carcinoma 5 1.2 Current clinical treatment strategy for HCC 6 1.3 T cell exhaustion in TME 9 1.4 Environmental factors in TME 10 1.5 Immune-based therapy for HCC 11 1.5.1 Combinatory therapy 11 1.5.2 T cell-based therapy 13 1.6 Comparison for different HCC mouse models 15 1.7 The HDI-based spontaneous HCC mouse model 16 2. Specific Aim 18 3. Material and method 19 3.1 Mice 19 3.2 Hydrodynamic injection (HDI) 19 3.3 Treatment strategy 20 3.4 Adoptive T cell transfer 20 3.5Lymphocytes isolated from the liver 21 3.6 Cell staining and flow cytometry analysis 21 3.7 In vitro T cell activation 22 3.8 Histology 22 3.9 Statistic analysis 23 4. Results 24 4.1 Nras and PTEN-p53/Cas9 worked synergistically to induce HCC in mice 24 4.2 Tumor cells expressed OVAI/II peptide to activate the antigen-specific T cells in HBsAg-HCC model 25 4.3 Antigen-specific CD4 T cells did not become exhausted in HBsAg-HCC mouse model 27 4.4 Adoptive transfer of CD8 T cells in early week eradicated the tumor in HBsAg-HCC mouse model 28 4.5 Antigen-specific CD8 T cell became exhaustion in HBsAg-HCC model 29 4.6 Combined lenvatinib with anti-PD1 controled tumor growth in the HBsAg-HCC model 31 5. Discussion 33 5.1 Brief summary 33 5.2 The advantage of the HDI-based spontaneous HCC mouse model 33 5.3 Cell infiltration of TME in the spontaneous HCC mouse model 34 5.4 Activation of the CD4 and CD8 T cells in HCC mouse model 35 5.5 The exhaustion state of the TSA-specific CD8 T cells in HCC mouse model 36 5.6 The effect of the combinatory therapy on TSA-specific T cells 37 Figure 39 Figure 1. The kinetics of the HBsAg-PTEN-p53/Nras-OVAI/II HCC mouse model at the different dosage 41 Figure 2. Expression of OVAⅠ peptide by tumor cells to induce CD8 T cells proliferation in the HBsAg-HCC mouse model. 43 Figure 3. Proliferation of CD4 T cells in LN following the damage of hepatocytes by HDI in HBsAg-HCC mouse model 45 Figure 4. The expression of the exhaustion markers on antigen-specific CD4 T cells in the HBsAg-HCC model 47 Figure 5. The expression of exhaustion markers on the antigen-specific CD8 T cells transferred in an early tumor stage 49 Figure 6. Exhaustive phenotypes of antigen-specific CD8 T cells in the HBsAg-HCC mouse model 52 Figure 7. The expression of the exhaustion markers on antigen-specific CD8 T in different weeks 54 Figure 8. The effect of the immune-based therapy on antigen-specific CD8 T cells in HBsAg-HCC model 57 | |
dc.language.iso | en | |
dc.title | 在原發性肝癌小鼠探討肝癌臨床用藥結合免疫療法對腫瘤抗原特異性T細胞的影響 | zh_TW |
dc.title | The effects of Lenvatinib combined with anti-PD1 on antigen-specific T cells in spontaneous hepatocellular carcinoma mouse model | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林俊彥(Chun-Yen Lin),陶秘華(Mi-Hua Tao),曾岱宗(Tai-Chung Tseng) | |
dc.subject.keyword | 原發性肝癌小鼠模型,合併免疫治療,抗原特異性T細胞, | zh_TW |
dc.subject.keyword | spontaneous HCC model,immune-based combinatory therapy,Ag-specific T cell, | en |
dc.relation.page | 59 | |
dc.identifier.doi | 10.6342/NTU202003234 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-08-15 | |
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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