請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82990完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林亮音(Liang-In Lin) | |
| dc.contributor.author | Ching-Hung Hsieh | en |
| dc.contributor.author | 謝慶宏 | zh_TW |
| dc.date.accessioned | 2022-11-25T08:04:26Z | - |
| dc.date.copyright | 2022-02-18 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-01-26 | |
| dc.identifier.citation | Villanueva, A., Hepatocellular Carcinoma. N Engl J Med, 2019. 380(15): p. 1450-1462. Llovet, J.M., et al., Hepatocellular carcinoma. Nat Rev Dis Primers, 2016. 2: p. 16018. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol, 2018. 69(1): p. 182-236. Llovet, J.M., et al., Hepatocellular carcinoma. Nat Rev Dis Primers, 2021. 7(1): p. 6. Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014. 74(11): p. 2913-21. Marrero, J.A., et al., Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology, 2018. 68(2): p. 723-750. Akinyemiju, T., et al., The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol, 2017. 3(12): p. 1683-1691. Kanwal, F., et al., Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology, 2017. 153(4): p. 996-1005.e1. Jepsen, P., et al., Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a Danish nationwide cohort study. Ann Intern Med, 2012. 156(12): p. 841-7, w295. Estes, C., et al., Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology, 2018. 67(1): p. 123-133. Llovet, J.M., C. Brú, and J. Bruix, Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis, 1999. 19(3): p. 329-38. Llovet, J.M., et al., Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference. Hepatology, 2021. 73 Suppl 1: p. 158-191. Shrager, B., et al., Resection of hepatocellular carcinoma without cirrhosis. Ann Surg, 2012. 255(6): p. 1135-43. Mazzaferro, V., et al., Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med, 1996. 334(11): p. 693-9. Heimbach, J.K., et al., AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology, 2018. 67(1): p. 358-380. Zhou, X.D., et al., Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer, 2001. 91(8): p. 1479-86. Yao, F.Y., et al., Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology, 2015. 61(6): p. 1968-77. Llovet, J.M. and J. Bruix, Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology, 2003. 37(2): p. 429-42. Llovet, J.M., et al., Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet, 2002. 359(9319): p. 1734-9. Lo, C.M., et al., Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology, 2002. 35(5): p. 1164-71. Bruix, J., et al., Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol, 2017. 67(5): p. 999-1008. Kudo, M., et al., Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet, 2018. 391(10126): p. 1163-1173. Finn, R.S., et al., Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med, 2020. 382(20): p. 1894-1905. Finn, R.S., et al., IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). Journal of Clinical Oncology, 2021. 39(3_suppl): p. 267-267. Nishimura, H., et al., Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol, 1998. 10(10): p. 1563-72. Nishimura, H., et al., Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 1999. 11(2): p. 141-51. Ansari, M.J., et al., The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med, 2003. 198(1): p. 63-9. Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med, 2012. 366(26): p. 2443-54. Linsley, P.S. and J.A. Ledbetter, The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol, 1993. 11: p. 191-212. Leach, D.R., M.F. Krummel, and J.P. Allison, Enhancement of antitumor immunity by CTLA-4 blockade. Science, 1996. 271(5256): p. 1734-6. Chambers, C.A., et al., CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol, 2001. 19: p. 565-94. Fife, B.T. and J.A. Bluestone, Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev, 2008. 224: p. 166-82. Poschke, I., D. Mougiakakos, and R. Kiessling, Camouflage and sabotage: tumor escape from the immune system. Cancer Immunol Immunother, 2011. 60(8): p. 1161-71. Buchbinder, E.I. and A. Desai, CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol, 2016. 39(1): p. 98-106. Sharma, P. and J.P. Allison, The future of immune checkpoint therapy. Science, 2015. 348(6230): p. 56-61. Förster, R., et al., A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell, 1996. 87(6): p. 1037-47. Ansel, K.M., et al., A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature, 2000. 406(6793): p. 309-14. del Molino del Barrio, I., J. Kirby, and S. Ali, The Role of Chemokine and Glycosaminoglycan Interaction in Chemokine-Mediated Migration In Vitro and In Vivo. Methods Enzymol, 2016. 570: p. 309-33. Meijer, J., et al., The CXCR5 chemokine receptor is expressed by carcinoma cells and promotes growth of colon carcinoma in the liver. Cancer Res, 2006. 66(19): p. 9576-82. Zhu, Z., et al., CXCL13-CXCR5 axis promotes the growth and invasion of colon cancer cells via PI3K/AKT pathway. Mol Cell Biochem, 2015. 400(1-2): p. 287-95. Wu, W., et al., Prognostic significance of CXCL12, CXCR4, and CXCR7 in patients with breast cancer. Int J Clin Exp Pathol, 2015. 8(10): p. 13217-24. Müller, G. and M. Lipp, Signal transduction by the chemokine receptor CXCR5: structural requirements for G protein activation analyzed by chimeric CXCR1/CXCR5 molecules. Biol Chem, 2001. 382(9): p. 1387-97. El-Haibi, C.P., et al., Differential G protein subunit expression by prostate cancer cells and their interaction with CXCR5. Mol Cancer, 2013. 12: p. 64. Thommen, D.S., et al., A transcriptionally and functionally distinct PD-1(+) CD8(+) T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med, 2018. 24(7): p. 994-1004. Razis, E., et al., The Role of CXCL13 and CXCL9 in Early Breast Cancer. Clin Breast Cancer, 2020. 20(1): p. e36-e53. Zhang, G., et al., CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer. Cancer Res Treat, 2020. 52(2): p. 622-633. Jiao, F., et al., Association of CXCL13 and Immune Cell Infiltration Signature in Clear Cell Renal Cell Carcinoma. Int J Med Sci, 2020. 17(11): p. 1610-1624. McLane, L.M., M.S. Abdel-Hakeem, and E.J. Wherry, CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol, 2019. 37: p. 457-495. Wherry, E.J. and M. Kurachi, Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol, 2015. 15(8): p. 486-99. Kasprowicz, V., et al., High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J Virol, 2008. 82(6): p. 3154-60. Bengsch, B., et al., Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog, 2010. 6(6): p. e1000947. Blackburn, S.D., et al., Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol, 2009. 10(1): p. 29-37. Wherry, E.J., et al., Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity, 2007. 27(4): p. 670-84. Wherry, E.J., et al., Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol, 2003. 77(8): p. 4911-27. Angelosanto, J.M., et al., Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J Virol, 2012. 86(15): p. 8161-70. Shin, H., et al., Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J Exp Med, 2007. 204(4): p. 941-9. Wherry, E.J., et al., Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci U S A, 2004. 101(45): p. 16004-9. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012. 12(4): p. 252-64. Wei, S.C., C.R. Duffy, and J.P. Allison, Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov, 2018. 8(9): p. 1069-1086. Hegde, P.S. and D.S. Chen, Top 10 Challenges in Cancer Immunotherapy. Immunity, 2020. 52(1): p. 17-35. Hamid, O., et al., Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol, 2019. 30(4): p. 582-588. Seder, R.A., P.A. Darrah, and M. Roederer, T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol, 2008. 8(4): p. 247-58. Hoogeveen, R.C. and A. Boonstra, Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection. Front Immunol, 2020. 11: p. 401. Fisicaro, P., et al., Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches. Front Immunol, 2020. 11: p. 849. Berraondo, P., et al., Cytokines in clinical cancer immunotherapy. Br J Cancer, 2019. 120(1): p. 6-15. Dinarello, C.A., Proinflammatory cytokines. Chest, 2000. 118(2): p. 503-8. Adachi, O., et al., Gene transfer of Fc-fusion cytokine by in vivo electroporation: application to gene therapy for viral myocarditis. Gene Therapy, 2002. 9(9): p. 577-583. Conlon, K.C., M.D. Miljkovic, and T.A. Waldmann, Cytokines in the Treatment of Cancer. J Interferon Cytokine Res, 2019. 39(1): p. 6-21. Koster, M.J. and K.J. Warrington, Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets. BMC Rheumatol, 2017. 1: p. 2. Palladino, M.A., et al., Anti-TNF-alpha therapies: the next generation. Nat Rev Drug Discov, 2003. 2(9): p. 736-46. Zhao, L., et al., The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice. Br J Cancer, 2002. 87(4): p. 465-70. Zheng, L., et al., Induction of apoptosis in mature T cells by tumour necrosis factor. Nature, 1995. 377(6547): p. 348-51. Mendoza, J.L., et al., Structure of the IFNγ receptor complex guides design of biased agonists. Nature, 2019. 567(7746): p. 56-60. Zhang, J., Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease. J Clin Invest, 2007. 117(4): p. 871-3. Ivashkiv, L.B., IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol, 2018. 18(9): p. 545-558. Pearce, E.L., et al., Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science, 2003. 302(5647): p. 1041-3. Intlekofer, A.M., et al., Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol, 2005. 6(12): p. 1236-44. Ravichandran, G., et al., Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol, 2019. 71(4): p. 773-782. Hsu, C.L., et al., Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma. Liver Cancer, 2021. 10(4): p. 346-359. Ou, D.L., et al., Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma. Liver Cancer, 2019. 8(3): p. 155-171. Zhao, M., et al., Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation. PLoS Pathog, 2020. 16(6): p. e1008555. Attanasio, J. and E.J. Wherry, Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity, 2016. 44(5): p. 1052-68. Jin, H.T., et al., Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A, 2010. 107(33): p. 14733-8. Johnston, R.J., et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell, 2014. 26(6): p. 923-937. Fuertes Marraco, S.A., et al., Inhibitory Receptors Beyond T Cell Exhaustion. Front Immunol, 2015. 6: p. 310. Dyck, L. and K.H.G. Mills, Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol, 2017. 47(5): p. 765-779. Jiang, W., et al., Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy. Front Immunol, 2020. 11: p. 622509. Collier, J.L., et al., Not-so-opposite ends of the spectrum: CD8(+) T cell dysfunction across chronic infection, cancer and autoimmunity. Nat Immunol, 2021. 22(7): p. 809-819. Kurachi, M., CD8(+) T cell exhaustion. Semin Immunopathol, 2019. 41(3): p. 327-337. Liu, Y., et al., IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol, 2021. 22(3): p. 358-369. Kelkar, M.G., et al., CD8 + T Cells Exhibit an Exhausted Phenotype in Hemophagocytic Lymphohistiocytosis. J Clin Immunol, 2021. Taghiloo, S., et al., Frequency and functional characterization of exhausted CD8(+) T cells in chronic lymphocytic leukemia. Eur J Haematol, 2017. 98(6): p. 622-631. Iga, N., et al., Accumulation of exhausted CD8+ T cells in extramammary Paget's disease. PLoS One, 2019. 14(1): p. e0211135. Ando, M., et al., Memory T cell, exhaustion, and tumor immunity. Immunol Med, 2020. 43(1): p. 1-9. Hudson, W.H., et al., Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1(+) Stem-like CD8(+) T Cells during Chronic Infection. Immunity, 2019. 51(6): p. 1043-1058.e4. Belizário, J. and M.F. Destro Rodrigues, Checkpoint inhibitor blockade and epigenetic reprogrammability in CD8(+) T-cell activation and exhaustion. Ther Adv Vaccines Immunother, 2020. 8: p. 2515135520904238. Zeng, Z., F. Wei, and X. Ren, Exhausted T cells and epigenetic status. Cancer Biol Med, 2020. 17(4): p. 923-936. Dong, C., Cytokine Regulation and Function in T Cells. Annu Rev Immunol, 2021. 39: p. 51-76. Alfei, F., et al., TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature, 2019. 571(7764): p. 265-269. Seo, H., et al., TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion. Proc Natl Acad Sci U S A, 2019. 116(25): p. 12410-12415. Muroyama, Y. and E.J. Wherry, Memory T-Cell Heterogeneity and Terminology. Cold Spring Harb Perspect Biol, 2021. Farhood, B., M. Najafi, and K. Mortezaee, CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: A review. J Cell Physiol, 2019. 234(6): p. 8509-8521. Li, H., et al., Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell, 2019. 176(4): p. 775-789.e18. Kallies, A., D. Zehn, and D.T. Utzschneider, Precursor exhausted T cells: key to successful immunotherapy? Nat Rev Immunol, 2020. 20(2): p. 128-136. Im, S.J. and S.J. Ha, Re-defining T-Cell Exhaustion: Subset, Function, and Regulation. Immune Netw, 2020. 20(1): p. e2. Barber, D.L., et al., Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006. 439(7077): p. 682-7. Sandu, I., et al., Landscape of Exhausted Virus-Specific CD8 T Cells in Chronic LCMV Infection. Cell Rep, 2020. 32(8): p. 108078. Sandu, I., et al., Exhausted CD8(+) T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection. Nat Commun, 2020. 11(1): p. 4454. Saeidi, A., et al., T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses. Front Immunol, 2018. 9: p. 2569. Zajac, A.J., et al., Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med, 1998. 188(12): p. 2205-13. Gallimore, A., et al., Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med, 1998. 187(9): p. 1383-93. Cheng, H., et al., The tumor microenvironment shapes the molecular characteristics of exhausted CD8(+) T cells. Cancer Lett, 2021. 506: p. 55-66. Pauken, K.E. and E.J. Wherry, Overcoming T cell exhaustion in infection and cancer. Trends Immunol, 2015. 36(4): p. 265-76. Xie, Q., J. Ding, and Y. Chen, Role of CD8(+) T lymphocyte cells: Interplay with stromal cells in tumor microenvironment. Acta Pharm Sin B, 2021. 11(6): p. 1365-1378. Waldman, A.D., J.M. Fritz, and M.J. Lenardo, A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol, 2020. 20(11): p. 651-668. Ostroumov, D., et al., CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci, 2018. 75(4): p. 689-713. van der Leun, A.M., D.S. Thommen, and T.N. Schumacher, CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer, 2020. 20(4): p. 218-232. Ma, Q.Y., J. Chen, and J. Zhao, Follicular cytotoxic CD8 T cells present high cytokine expression, and are more susceptible to Breg-mediated suppression in non-small cell lung cancer. Immunol Res, 2020. 68(1): p. 54-62. Yu, D. and L. Ye, A Portrait of CXCR5(+) Follicular Cytotoxic CD8(+) T cells. Trends Immunol, 2018. 39(12): p. 965-979. Armas-González, E., et al., Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis. Arthritis Research Therapy, 2018. 20(1): p. 114. Ansel, K.M., R.B. Harris, and J.G. Cyster, CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity, 2002. 16(1): p. 67-76. Pereira, J.P., L.M. Kelly, and J.G. Cyster, Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int Immunol, 2010. 22(6): p. 413-9. Cosgrove, J., et al., B cell zone reticular cell microenvironments shape CXCL13 gradient formation. Nature Communications, 2020. 11(1): p. 3677. Kowarik, M.C., et al., CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. Journal of Neuroinflammation, 2012. 9(1): p. 93. Gunn, M.D., et al., A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature, 1998. 391(6669): p. 799-803. Legler, D.F., et al., B Cell–attracting Chemokine 1, a Human CXC Chemokine Expressed in Lymphoid Tissues, Selectively Attracts B Lymphocytes via BLR1/CXCR5. Journal of Experimental Medicine, 1998. 187(4): p. 655-660. Maecker, H.T., J.P. McCoy, and R. Nussenblatt, Standardizing immunophenotyping for the Human Immunology Project. Nat Rev Immunol, 2012. 12(3): p. 191-200. Robinson, J.P. and M. Roederer, HISTORY OF SCIENCE. Flow cytometry strikes gold. Science, 2015. 350(6262): p. 739-40. Park, L.M., J. Lannigan, and M.C. Jaimes, OMIP-069: Forty-Color Full Spectrum Flow Cytometry Panel for Deep Immunophenotyping of Major Cell Subsets in Human Peripheral Blood. Cytometry A, 2020. 97(10): p. 1044-1051. Spitzer, M.H. and G.P. Nolan, Mass Cytometry: Single Cells, Many Features. Cell, 2016. 165(4): p. 780-91. Bandura, D.R., et al., Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem, 2009. 81(16): p. 6813-22. Sahir, F., et al., Development of a 43 color panel for the characterization of conventional and unconventional T-cell subsets, B cells, NK cells, monocytes, dendritic cells, and innate lymphoid cells using spectral flow cytometry. Cytometry A, 2020. Novo, D., G. Grégori, and B. Rajwa, Generalized unmixing model for multispectral flow cytometry utilizing nonsquare compensation matrices. Cytometry A, 2013. 83(5): p. 508-20. Ferrer-Font, L., et al., Panel Design and Optimization for High-Dimensional Immunophenotyping Assays Using Spectral Flow Cytometry. Curr Protoc Cytom, 2020. 92(1): p. e70. Shen, F.-W., J.-S. Tung, and E.A. Boyse, Further definition of the Ly-5 system. Immunogenetics, 1986. 24(3): p. 146-149. Zebedee, S.L., D.S. Barritt, and W.C. Raschke, Comparison of mouse Ly5a and Ly5b leucocyte common antigen alleles. Dev Immunol, 1991. 1(4): p. 243-54. Shen, F., Monoclonal Antibodies and T Cell Hybridomas: Perspectives and Technical Advances. 1981, Elsiever/North-Holland Biomedical Press Amsterdam, the Netherlands. Durgeau, A., et al., Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy. Frontiers in immunology, 2018. 9: p. 14-14. Boon, T., P.G. Coulie, and B. Van den Eynde, Tumor antigens recognized by T cells. Immunol Today, 1997. 18(6): p. 267-8. Fu, C. and A. Jiang, Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment. Front Immunol, 2018. 9: p. 3059. Cheng, Y., et al., Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma. Immunity, 2021. 54(8): p. 1825-1840.e7. Schenkel, J.M., et al., Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1(+) CD8(+) T cells in tumor-draining lymph nodes. Immunity, 2021. 54(10): p. 2338-2353.e6. Eberhardt, C.S., et al., Functional HPV-specific PD-1(+) stem-like CD8 T cells in head and neck cancer. Nature, 2021. 597(7875): p. 279-284. Papalexi, E. and R. Satija, Single-cell RNA sequencing to explore immune cell heterogeneity. Nature Reviews Immunology, 2018. 18(1): p. 35-45. Wu, F., et al., Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nature Communications, 2021. 12(1): p. 2540. Junttila, M.R. and F.J. de Sauvage, Influence of tumour micro-environment heterogeneity on therapeutic response. Nature, 2013. 501(7467): p. 346-354. Wherry, E.J., T cell exhaustion. Nat Immunol, 2011. 12(6): p. 492-9. Chen, Z., et al., TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision. Immunity, 2019. 51(5): p. 840-855.e5. Hashimoto, M., et al., CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med, 2018. 69: p. 301-318. Miller, B.C., et al., Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol, 2019. 20(3): p. 326-336. Siddiqui, I., et al., Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity, 2019. 50(1): p. 195-211.e10. Yost, K.E., et al., Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med, 2019. 25(8): p. 1251-1259. Wan, C., et al., Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer. Cancer Res, 2021. 81(1): p. 158-173. Kim, K., et al., Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Med, 2020. 12(1): p. 22. Huang, A.C., et al., T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature, 2017. 545(7652): p. 60-65. Franco, F., et al., Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab, 2020. 2(10): p. 1001-1012. Fischer, K., et al., Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood, 2007. 109(9): p. 3812-9. Rodriguez, P.C., et al., Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res, 2009. 69(4): p. 1553-60. Speiser, D.E., P.C. Ho, and G. Verdeil, Regulatory circuits of T cell function in cancer. Nat Rev Immunol, 2016. 16(10): p. 599-611. Ma, J., et al., PD1(Hi) CD8(+) T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer, 2019. 7(1): p. 331. Blank, C.U., et al., Defining 'T cell exhaustion'. Nat Rev Immunol, 2019. 19(11): p. 665-674. Winkler, F. and B. Bengsch, Use of Mass Cytometry to Profile Human T Cell Exhaustion. Front Immunol, 2019. 10: p. 3039. Shen, Y., et al., PD-1 does not mark tumor-infiltrating CD8+ T cell dysfunction in human gastric cancer. J Immunother Cancer, 2020. 8(2). Ahn, E., et al., Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci U S A, 2018. 115(18): p. 4749-4754. Taggart, D., et al., Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8(+) T cell trafficking. Proc Natl Acad Sci U S A, 2018. 115(7): p. E1540-e1549. Kamphorst, A.O., et al., Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A, 2017. 114(19): p. 4993-4998. Miller, B.C., et al., Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nature Immunology, 2019. 20(3): p. 326-336. Hurkmans, D.P., et al., Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer. Journal for ImmunoTherapy of Cancer, 2020. 8(1): p. e000586. Wang, D.Y., et al., Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol, 2018. 4(12): p. 1721-1728. Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med, 2018. 378(14): p. 1277-1290. Gooley, T.A., et al., Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med, 2010. 363(22): p. 2091-101. Eggermont, A.M., et al., Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med, 2016. 375(19): p. 1845-1855. Weber, J.S., K.C. Kähler, and A. Hauschild, Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol, 2012. 30(21): p. 2691-7. Xu, C., et al., Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. Bmj, 2018. 363: p. k4226. Martins, F., et al., Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 2019. 16(9): p. 563-580. Herbst, R.S., et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016. 387(10027): p. 1540-1550. Kaufman, H.L., et al., Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol, 2016. 17(10): p. 1374-1385. Hellmann, M.D., et al., Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med, 2018. 378(22): p. 2093-2104. Xu, T., et al., Identification of CXCL13 as a potential biomarker in clear cell renal cell carcinoma via comprehensive bioinformatics analysis. Biomed Pharmacother, 2019. 118: p. 109264. Huang, B., et al., Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients. Cancer Cell Int, 2020. 20: p. 195. Duan, Z., et al., Phenotype and function of CXCR5+CD45RA-CD4+ T cells were altered in HBV-related hepatocellular carcinoma and elevated serum CXCL13 predicted better prognosis. Oncotarget, 2015. 6(42): p. 44239-53. Zhu, D., W. Ye, and J. Jiang, Clinical significance of CXCL13/CXCR5 axis in human cancers. Translational Cancer Research, 2018. 7(6): p. 1737-1742. Biswas, S., et al., CXCL13-CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis. Breast Cancer Res Treat, 2014. 143(2): p. 265-76. Qi, X.W., et al., Expression features of CXCR5 and its ligand, CXCL13 associated with poor prognosis of advanced colorectal cancer. Eur Rev Med Pharmacol Sci, 2014. 18(13): p. 1916-24. Razis, E., et al., Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression. Clin Breast Cancer, 2012. 12(3): p. 183-93. Suo, A., et al., Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma. Oncologist, 2020. 25(5): p. 438-446. Kwok, G., et al., Pembrolizumab (Keytruda). Hum Vaccin Immunother, 2016. 12(11): p. 2777-2789. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82990 | - |
| dc.description.abstract | 2018年諾貝爾生醫獎得主Tasuku Honjo和James Allison，分別發現了anti-PD-1和anti-CTLA4應用於癌症病患上，對癌症患者帶來了前所未有的治療效果。然而，這一類免疫檢查點抑制劑的治療平均約只對2-3成的病患是有效的。另一方面，這一類治療藥物的價格相當昂貴，如何在治療前就能精準的預測其對藥物的敏感性，找到對於這類藥物治療的predictive markers，是目前臨床上急需解決的問題。實驗室過去透過肝癌病人在接受免疫檢查點抑制劑(anti-PD-1/anti-PD-L1)治療前所取得的腫瘤檢體進行分析，對比其治療之後的效果，找到與衰竭性CD8 T細胞是呈現高相關性，並且分析出其中的9個基因，是可以成功的預測肝癌病人在接受anti-PD-1/anti-PD-L1後的治療成果，其中包含了CXCL13。然而，衰竭性CD8 T細胞與CXCL13在anti-PD-1/anti-PD-L1治療的關聯與角色是不了解的。因此本論文主要目標分成三個部份：（1）建立體外(ex vivo)的方式，誘導出衰竭性CD8 T細胞；（2）了解衰竭性CD8 T細胞對免疫檢查點抑制劑(anti-PD-1/anti-PD-L1)的作用機制；（3）了解CXCL13在免疫檢查點抑制劑(anti-PD-1/anti-PD-L1)所產生之反應的機制。首先，我們以體外(ex vivo)的方式誘導出衰竭性CD8 T細胞，我們利用基因轉殖鼠―P14小鼠，因CD8 T細胞能專一性辨識gp33抗原，以體外的方式重複且長時間的刺激下，誘導出衰竭性CD8 T細胞，並利用相關markers定義衰竭性CD8 T細胞。進一步我們在功能性試驗上，進行細胞毒殺實驗，證明衰竭性CD8 T細胞與活化態CD8 T細胞相比，其具有較差的毒殺能力。接著我們更深入的與傳統體內獲得的衰竭性CD8 T細胞比較，證實有著相同的特性，並進一步發現anti-PD-1對腫瘤治療的效果是針對腫瘤微環境中的浸潤淋巴球，使其恢復活性，而達到治療的療效。在實驗中，我們發現了衰竭性和活化態CD8 T細胞，其CXCL13最主要的receptor―CXCR5會明顯上升，並且在migration assay上證實衰竭性和活化態CD8 T細胞都能被CXCL13所吸引，並且是有著劑量依賴性(dose dependent)的特性。我們在肝癌的臨床病人上發現腫瘤細胞會分泌CXCL13，並且CXCL13的分泌與anti-PD-1/anti-PD-L1的治療效果是呈現正相關。該研究結果證實，當腫瘤細胞分泌CXCL13時，吸引許多免疫細胞浸潤，並且在接受anti-PD-1的治療下，腫瘤浸潤的淋巴球恢復其活性，進而毒殺腫瘤細胞，使腫瘤明顯較小。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T08:04:26Z (GMT). No. of bitstreams: 1 U0001-2912202121501600.pdf: 8562219 bytes, checksum: ba3258adcc13332848f4efc0fccd598a (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | "誌謝 i 摘要 ii Abstract iv 目錄 vii 緒論 1 1 肝癌（Hepatocellular Carcinoma, HCC） 1 2 免疫檢查點抑制劑（Immune Checkpoint Inhibitors） 2 3 C-X-C motif chemokine ligand 13 (CXCL13) 3 4 衰竭性CD8 T細胞(exhausted CD8+ T cells) 3 5 作用型細胞激素(effector cytokines) 4 6 實驗室過去的研究結果 5 7 論文研究的目的 5 材料與方法 7 1 實驗材料 7 1.1 細胞培養 7 1.2 藥物 7 1.4 小髮夾RNA(shRNA) 11 1.5 質體 11 1.6 細菌培養 12 1.7 基因轉染 (Transfection) 12 1.8 質體純化試劑 12 1.9 即時聚合酶連鎖反應(real-time PCR) 12 1.10 腫瘤浸潤淋巴球(tumor infiltrating lymphocytes，簡稱TILs)分取試劑 12 1.11 特異性CD8 T細胞染色 13 1.12 動物實驗 13 2 實驗方法 13 2.1 細胞培養 (Cell culture) 13 2.2 取脾臟細胞 (splenocyte) 14 2.3 流式細胞儀（Flow cytometry） 14 2.4 過量表現（Overexpression）蛋白 16 2.5 DNA相關實驗 16 2.6 即時聚合酶連鎖反應(real-time PCR) 17 2.7 酵素免疫吸附法(ELISA) 19 2.8 腫瘤浸潤淋巴球(tumor infiltrating lymphocytes，簡稱TIL)分取 21 2.9 毒殺試驗 23 2.10 功能性試驗 (Functional assay) 23 2.11 免疫組織化學染色 (IHC) 23 2.12 RNA原位雜合技術(RNA in situ hybridization RNAscope® assay) 25 2.13 細胞遷移試驗(migration assay) 26 2.14 特異性CD8 T細胞染色 27 2.15 動物實驗 27 2.16 統計分析 28 實驗結果 29 1. 建立在體外實驗下(ex vivo)誘導出CD8 T細胞呈現衰竭的現象 29 2. 透過流式細胞儀的方式，證實體外實驗的衰竭性CD8 T細胞 29 3. 利用毒殺試驗，進一步證實體外誘導的衰竭性CD8 T細胞 30 4. Anti-PD-1可使腫瘤浸潤CD8 T細胞恢復功能，達到毒殺腫瘤的治療效果 31 5. 衰竭性CD8 T細胞表現高比例的CXCR5，並且對CXCL13有趨向性 33 6. 以免疫組織化學染色(Immunohistochemistry, IHC)、RNA雜交和多色螢光的方式，證實當病人的腫瘤細胞分泌CXCL13時，對免疫檢查點抑制劑(anti-PD-1/anti-PD-L1)的治療效果較佳 34 7. 在Hepa1-6小鼠肝癌細胞株中，過度表現CXCL13 34 8. 以Cytek 光譜式流式細胞儀的實驗平台，測試並驗證我們體外誘導的衰竭性CD8 T細胞 35 9. 將P14小鼠基因轉殖為P14 CD45.1小鼠 36 10. 建立偵測特異性CD8 T細胞(specific CD8 T cell)的平台 37 討論 39 實驗結果圖 45 附圖 74 附件 76 參考文獻 82" | |
| dc.language.iso | zh-TW | |
| dc.subject | 衰竭性CD8 T細胞 | zh_TW |
| dc.subject | 腫瘤微環境 | zh_TW |
| dc.subject | 免疫檢查點抑制劑 | zh_TW |
| dc.subject | 免疫療法 | zh_TW |
| dc.subject | CXCL13 | zh_TW |
| dc.subject | immune checkpoint inhibitors | en |
| dc.subject | exhausted CD8 T cell | en |
| dc.subject | immunotherapy | en |
| dc.subject | CXCL13 | en |
| dc.subject | tumor microenvironment | en |
| dc.title | 探討CXCL13與CD8 T細胞耗竭對於免疫調控劑治療在肝細胞癌角色 | zh_TW |
| dc.title | Exploring of CXCL13 and exhausted CD8 T cells to immune checkpoint inhibitor therapy for hepatocellular carcinoma | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 許駿(Chiun Hsu),歐大諒(Da-Liang Ou) | |
| dc.contributor.oralexamcommittee | 胡忠怡(Hsin-Tsai Liu),蘇剛毅(Chih-Yang Tseng) | |
| dc.subject.keyword | CXCL13,免疫療法,免疫檢查點抑制劑,衰竭性CD8 T細胞,腫瘤微環境, | zh_TW |
| dc.subject.keyword | CXCL13,immunotherapy,immune checkpoint inhibitors,exhausted CD8 T cell,tumor microenvironment, | en |
| dc.relation.page | 94 | |
| dc.identifier.doi | 10.6342/NTU202104597 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2022-01-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-01-01 | - |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-2912202121501600.pdf 未授權公開取用 | 8.36 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。