肺腫瘤微環境生物晶片的開發以探討白血球介素-6驅動的T淋巴細胞之活化與遷移

簡易檢索 / 詳目顯示

回結果列表

研究生：	蝴蝶 Parvaneh Sardarabadi
論文名稱：	肺腫瘤微環境生物晶片的開發以探討白血球介素-6驅動的T淋巴細胞之活化與遷移 Exploring IL-6-Driven T-Cell Activation and Migration in a Lung-Tumor Microenvironment Biochip
指導教授：	劉承賢 Liu, Cheng-Hsien
口試委員:	北森武彥 Kitamori, Takehiko 李岡遠 Lee, Kang-Yun 涂夏爾 Punde, Tushar 孫偉倫 Sun, Wei-Lun
學位類別：	博士 Doctor
系所名稱：	工學院 - 奈米工程與微系統研究所 Institute of NanoEngineering and MicroSystems
論文出版年：	2024
畢業學年度：	113
語文別：	英文
論文頁數：	121
中文關鍵詞：	6 、白細胞介素-6（IL-6) 、趨化因子、T細胞活化、腫瘤微環境（TME）、三維培養、免疫細胞遷移
外文關鍵詞：	6, Interleukin-6 (IL-6), Chemokine, T-cell activation, Tumor microenvironment (TME), 3D culture, Immune cell migration
相關次數：	點閱：3 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

白細胞介素-6（IL-6）由免疫細胞產生，對於引導T細胞至感染和炎症部位具有重要作用，並影響多種生理和病理途徑。IL-6的濃度以及其他細胞因子和趨化因子的濃度，在指導T細胞分化和激活過程中發揮關鍵作用。首先，我們設計了一種流動型微系統，具有特定功能，可以在受控的3D培養環境中研究T細胞對不同IL-6濃度梯度的激活反應。該對稱晶片稀釋IL-6，從而在腔室內產生濃度梯度，使我們能夠系統地評估濃度梯度對免疫細胞行為的時間和劑量依賴性影響。之後，該晶片被改造成一個肺腫瘤微環境模型。在免疫細胞與癌細胞共培養中，CD標誌表達顯著上調，這表明IL-6濃度梯度顯著影響T細胞的表型。研究結果顯示，癌細胞對不同濃度的IL-6表現出濃度依賴的反應，免疫細胞的遷移率受IL-6濃度梯度的密切影響。理解IL-6在腫瘤微環境（TME）中的雙重角色對於釐清其作用至關重要。IL-6的複雜性在TME中呈現出動態的景觀。在3D仿真結構中探索這些複雜性，有助於理解趨化因子濃度動態與免疫和癌細胞反應之間的相互作用。

Interleukin-6 (IL-6), generated by immune cells, is critical in directing T cells to infection and inflammation sites, influencing numerous physiological and pathological pathways. IL-6 levels and concentrations of other cytokines and chemokines are crucial in guiding T-cell differentiation and activation processes. In the first step, we designed a flow-based microsystem with specific features to investigate T-cell activation in response to varying IL-6 gradients in a controlled 3D culture environment. The symmetric chip dilutes IL-6 to create concentration gradients within chambers, enabling systematic assessment of their time- and dose-dependent effects on immune cell behaviors. Later, the chip was modified into a lung-tumor microenvironment model. Co-cultures of immune cells with cancer cells showed a notable upregulation of CD marker expression, suggesting that IL-6 concentration gradients significantly influence T-cell phenotypes. The investigation revealed that cancer cells demonstrated a responsive, concentration-dependent reaction to different levels of IL-6, with immune cell migration rates closely influenced by the gradient of IL-6 concentrations. Understanding the dual roles of IL-6 within the tumor microenvironment (TME) is imperative to clarify its role. IL-6's intricate nature presents a dynamic landscape in TME. Exploring these complexities within a 3D mimetic structure helps understand the interplay between chemokine concentration dynamics and immune and cancer cell responses.

Abstract    2
中文摘要    3
Table of Contents    4
List of Tables    8
List of Figures    9
Acknowledgments    17
Abbreviation    19
Chapter 1: Introduction    21
1 Background and motivation    21
2 Research objectives    21
3 Research approach    22
4 Key findings and significance    23
5 Thesis outline    24
Chapter 2: Literature review    25
1 Chemotaxis    28
2 Interleukin-6 (IL-6)    29
2.1 Anti-tumor function    32
2.2 Pro-tumor function    33
3 Human T-cell development, localization, and function    34
3.1 T-cell activation    35
3.2 T-cell exhaustion    36
3.3 CD69    37
3.4 CD183 (CXCR3)    37
3.5 CCR6 (CD 196)    38
3.6 PD-1 (Programmed cell death protein-1) / PDL1 (Programmed death-ligand 1)    39
3.7 Interferon-gamma (IFN-γ)    40
3.8 Tumor necrosis factor alpha (TNF-α)    41
4 Tumor microenvironment (TME)    42
5 Non-small-cell lung cancer (NSCLC)    43
6 Characterization and applications of various cell culture models    44
6.1 2-dimensional cell culture (2D)    44
6.2 3-dimensional cell culture (3D)    45
6.3 Cell culture on biochip platforms: techniques and applications    45
7 Cell co-culture technique    46
7.1 Extracellular matrix (ECM) –hydrogel    46
Chapter 3: Materials and methods    48
1 Cell Preparation    48
1.1 Human lung adenocarcinoma cell line (A549)    48
1.2 Human immune T cells (Jurkat T)    48
1.3 Human fetal lung fibroblast, Wi-38 Cells    49
2 Recombinant active human IL-6 protein    49
3 Biocompatible material, Gelatin Methacryloyl (GelMA)    49
4 Cell tracker    50
5 LIVE/DEAD assay    51
6 COMSOL Multiphysics modeling    51
7 Experimental setup for fluorescence intensity measurement    53
8 Fluorescent microscope    55
9 Flow Cytometry    57
10 Enzyme-linked immunosorbent assay (ELISA)    58
11 High-Resolution Thermal Field Emission Scanning Microscopy (HRFEGSEM)    58
12 Microsystems design    59
13 Microfluidic chip fabrication    61
14 Experimental equipment setup    62
15 Structure and operating concept of the lung-TME chip    63
Chapter 4: Results    66
1 GelMA+ PEGDA hydrogels combination    66
1.1 Synthesis of gelatin methacrylate (GelMA)    67
1.2 Characteristics of gelatin methacrylate (GelMA)    67
2 Viability rate of A549 and Jurkat in GelMA (96-well plate & biochip)    71
3 Cell survival of A549 and Jurkat cells in varying IL-6 concentrations    72
3.1 Impact of IL6 concentrations on cell viability in A459 & Jurkat co-culture    73
4 Principles of the concentration system    75
5 Jurkat and Wi 38 co-culture in biochip (design-1) investigation of chemotaxis    77
5.1 Jurkat and Wi 38 co-cultured proliferation in biochip    77
5.2 Dilution of 250 ng IL-6 in biochip (design-1) investigation of chemotaxis    79
5.3 Impact of IL-6 on fibroblast proliferation    82
6 Jurkat and A549 co-culture in biochip    83
6.1 Gradient dilution of 200 ng/mL IL-6 in lung-TME chip    83
6.2 Gradient dilution of 100 ng/mL IL-6 in lung-TME chip    85
6.3 Gradient dilution of 50 ng/mL IL-6 in lung-TME chip    88
7 Effect of 200 ng/mL IL6 on cell viability in A549 and Jurkat co-culture in the lung-TME chip    90
8 Quantitative analysis of flow cytometry data    91
8.1 IL-6-Induced modulation of CD marker expression in Jurkat cell monoculture    92
8.2 IL-6-Induced modulation of CD marker expression in Jurkat cell co-cultured by A549 isolated from lung-TME chip    94
8.3 Characterization of CD4+CD8+ double-positive T cells in immune response studies    97
8.4 Relevance of exhaustion markers in T cells    97
9 IFN-γ and TNF-α monitoring    98
10 Application of the microfluidic device in clinical anti-cancer drug selection and chemotaxis investigation    101
Chapter 5: Discussion & Future Scope of Research    103
1 Discussion    103
2 Future scope of research    108
References    111
List of Publications    121

                                

(1) Wojas-Krawczyk, K.; Paśnik, I.; Kucharczyk, T.; Wieleba, I.; Krzyżanowska, N.; Gil, M.; Krawczyk, P.; Milanowski, J. Immunoprofiling: an encouraging method for predictive factors examination in lung cancer patients treated with immunotherapy. International Journal of Molecular Sciences 2021, 22 (17), 9133.
(2) Sanders, E.; Alcaide, P. Red light-green light: T-cell trafficking in cardiac and vascular inflammation. American Journal of Physiology-Cell Physiology 2023, 324 (1), C58-C66.
(3) Aliyu, M.; Zohora, F. T.; Anka, A. U.; Ali, K.; Maleknia, S.; Saffarioun, M.; Azizi, G. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. International Immunopharmacology 2022, 111, 109130.
(4) Fisher, D. T.; Appenheimer, M. M.; Evans, S. S. The two faces of IL-6 in the tumor microenvironment. In Seminars in immunology, 2014; Elsevier: Vol. 26, pp 38-47.
(5) Schumertl, T.; Lokau, J.; Rose-John, S.; Garbers, C. Function and proteolytic generation of the soluble interleukin-6 receptor in health and disease. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 2022, 1869 (1), 119143.
(6) Shekhawat, J.; Gauba, K.; Gupta, S.; Purohit, P.; Mitra, P.; Garg, M.; Misra, S.; Sharma, P.; Banerjee, M. Interleukin-6 perpetrator of the COVID-19 cytokine storm. Indian Journal of Clinical Biochemistry 2021, 36 (4), 440-450.
(7) Ridker, P. M.; Rane, M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circulation research 2021, 128 (11), 1728-1746.
(8) Nguyen, D. P.; Li, J.; Tewari, A. K. Inflammation and prostate cancer: the role of interleukin 6 (IL‐6). BJU international 2014, 113 (6), 986-992.
(9) Lippitz, B. E.; Harris, R. A. Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis. Oncoimmunology 2016, 5 (5), e1093722.
(10) Hulkower, K. I.; Herber, R. L. Cell migration and invasion assays as tools for drug discovery. Pharmaceutics 2011, 3 (1), 107-124.
(11) Berendsen, J. T.; Kruit, S. A.; Atak, N.; Willink, E.; Segerink, L. I. Flow-free microfluidic device for quantifying chemotaxis in spermatozoa. Analytical chemistry 2020, 92 (4), 3302-3306.
(12) Zommiti, M.; Connil, N.; Tahrioui, A.; Groboillot, A.; Barbey, C.; Konto-Ghiorghi, Y.; Lesouhaitier, O.; Chevalier, S.; Feuilloley, M. G. Organs-on-Chips platforms are everywhere: A zoom on biomedical investigation. Bioengineering 2022, 9 (11), 646.
(13) Van Os, L.; Engelhardt, B.; Guenat, O. T. Integration of immune cells in organs-on-chips: a tutorial. Frontiers in Bioengineering and Biotechnology 2023, 11, 1191104.
(14) Pinkerton, J. W.; Kim, R. Y.; Robertson, A. A.; Hirota, J. A.; Wood, L. G.; Knight, D. A.; Cooper, M. A.; O’Neill, L. A.; Horvat, J. C.; Hansbro, P. M. Inflammasomes in the lung. Molecular immunology 2017, 86, 44-55.
(15) Zhao, W.; Zhao, H.; Li, M.; Huang, C. Microfluidic devices for neutrophil chemotaxis studies. Journal of Translational Medicine 2020, 18, 1-19.
(16) Lin, F.; Butcher, E. C. T cell chemotaxis in a simple microfluidic device. Lab on a Chip 2006, 6 (11), 1462-1469.
(17) Frick, C.; Dettinger, P.; Renkawitz, J.; Jauch, A.; Berger, C. T.; Recher, M.; Schroeder, T.; Mehling, M. Nano-scale microfluidics to study 3D chemotaxis at the single cell level. PloS one 2018, 13 (6), e0198330.
(18) Mehling, M.; Frank, T.; Albayrak, C.; Tay, S. Real-time tracking, retrieval and gene expression analysis of migrating human T cells. Lab on a Chip 2015, 15 (5), 1276-1283.
(19) Liu, Y.; Ren, X.; Wu, J.; Wilkins, J. A.; Lin, F. T cells chemotaxis migration studies with a multi-channel microfluidic device. Micromachines 2022, 13 (10), 1567.
(20) Garcia-Seyda, N.; Aoun, L.; Tishkova, V.; Seveau, V.; Biarnes-Pelicot, M.; Bajenoff, M.; Valignat, M.-P.; Theodoly, O. Microfluidic device to study flow-free chemotaxis of swimming cells. Lab on a Chip 2020, 20 (9), 1639-1647.
(21) Sala, F.; Ficorella, C.; Osellame, R.; Käs, J. A.; Martínez Vázquez, R. Microfluidic lab-on-a-chip for studies of cell migration under spatial confinement. Biosensors 2022, 12 (8), 604.
(22) Li, X.; Valadez, A. V.; Zuo, P.; Nie, Z. Microfluidic 3D cell culture: potential application for tissue-based bioassays. Bioanalysis 2012, 4 (12), 1509-1525.
(23) Chung, B. G.; Choo, J. Microfluidic gradient platforms for controlling cellular behavior. Electrophoresis 2010, 31 (18), 3014-3027.
(24) Katsuta, E.; Rashid, O. M.; Takabe, K. Clinical relevance of tumor microenvironment: Immune cells, vessels, and mouse models. Human Cell 2020, 33 (4), 930-937.
(25) Dornhof, J.; Kieninger, J.; Muralidharan, H.; Maurer, J.; Urban, G. A.; Weltin, A. Microfluidic organ-on-chip system for multi-analyte monitoring of metabolites in 3D cell cultures. Lab on a Chip 2022, 22 (2), 225-239.
(26) Chaicharoenaudomrung, N.; Kunhorm, P.; Noisa, P. Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World journal of stem cells 2019, 11 (12), 1065.
(27) Chen, C.; Mehl, B. T.; Munshi, A. S.; Townsend, A. D.; Spence, D. M.; Martin, R. S. 3D-printed microfluidic devices: fabrication, advantages and limitations—a mini review. Analytical Methods 2016, 8 (31), 6005-6012.
(28) Sequeira, R. C.; Criswell, T.; Atala, A.; Yoo, J. J. Microfluidic systems for assisted reproductive technologies: Advantages and potential applications. Tissue engineering and regenerative medicine 2020, 17 (6), 787-800.
(29) Manes, S.; Gómez-Moutón, C.; Lacalle, R. A.; Jiménez-Baranda, S.; Mira, E.; Martínez-A, C. Mastering time and space: immune cell polarization and chemotaxis. In Seminars in immunology, 2005; Elsevier: Vol. 17, pp 77-86.
(30) Gago da Graça, C.; van Baarsen, L. G.; Mebius, R. E. Tertiary lymphoid structures: diversity in their development, composition, and role. The Journal of Immunology 2021, 206 (2), 273-281.
(31) Hughes, C. E.; Nibbs, R. J. A guide to chemokines and their receptors. The FEBS journal 2018, 285 (16), 2944-2971.
(32) Sokol, C. L.; Luster, A. D. The chemokine system in innate immunity. Cold Spring Harbor perspectives in biology 2015, 7 (5), a016303.
(33) Uciechowski, P.; Dempke, W. C. M. Interleukin-6: A Masterplayer in the Cytokine Network. Oncology 2020, 98 (3), 131-137. DOI: 10.1159/000505099 (acccessed 7/1/2024).
(34) Uciechowski, P.; Dempke, W. Interleukin-6: a masterplayer in the cytokine network. Oncology 2020, 98 (3), 131-137.
(35) Jones, B. E.; Maerz, M. D.; Buckner, J. H. IL-6: a cytokine at the crossroads of autoimmunity. Current opinion in immunology 2018, 55, 9-14.
(36) Strutt, T. M.; McKinstry, K. K.; Kuang, Y.; Finn, C. M.; Hwang, J. H.; Dhume, K.; Sell, S.; Swain, S. L. Direct IL-6 signals maximize protective secondary CD4 T cell responses against influenza. The Journal of Immunology 2016, 197 (8), 3260-3270.
(37) Kim, S.; Gwak, H.; Kim, H. S.; Kim, B.; Dhanasekaran, D. N.; Song, Y. S. Malignant ascites enhances migratory and invasive properties of ovarian cancer cells with membrane bound IL-6R in vitro. Oncotarget 2016, 7 (50), 83148.
(38) Heikkilä, K.; Ebrahim, S.; Lawlor, D. A. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. European journal of cancer 2008, 44 (7), 937-945.
(39) Kohli, K.; Pillarisetty, V. G.; Kim, T. S. Key chemokines direct migration of immune cells in solid tumors. Cancer gene therapy 2022, 29 (1), 10-21.
(40) Zhou, L.; Ivanov, I. I.; Spolski, R.; Min, R.; Shenderov, K.; Egawa, T.; Levy, D. E.; Leonard, W. J.; Littman, D. R. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature immunology 2007, 8 (9), 967-974.
(41) Wei, L.; Laurence, A.; Elias, K. M.; O'Shea, J. J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. Journal of biological chemistry 2007, 282 (48), 34605-34610.
(42) Rodríguez-Bayona, B.; Ramos-Amaya, A.; López-Blanco, R.; Campos-Caro, A.; Brieva, J. A. STAT-3 activation by differential cytokines is critical for human in vivo–generated plasma cell survival and Ig secretion. The Journal of Immunology 2013, 191 (10), 4996-5004.
(43) Tsukamoto, H.; Fujieda, K.; Hirayama, M.; Ikeda, T.; Yuno, A.; Matsumura, K.; Fukuma, D.; Araki, K.; Mizuta, H.; Nakayama, H. Soluble IL6R expressed by myeloid cells reduces tumor-specific Th1 differentiation and drives tumor progression. Cancer Research 2017, 77 (9), 2279-2291.
(44) Tsukamoto, H.; Fujieda, K.; Senju, S.; Ikeda, T.; Oshiumi, H.; Nishimura, Y. Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity. Cancer science 2018, 109 (3), 523-530.
(45) Jones, S. A.; Jenkins, B. J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nature reviews immunology 2018, 18 (12), 773-789.
(46) Neufert, C.; Becker, C.; Wirtz, S.; Fantini, M. C.; Weigmann, B.; Galle, P. R.; Neurath, M. F. IL‐27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. European journal of immunology 2007, 37 (7), 1809-1816.
(47) Kitabayashi, C.; Fukada, T.; Kanamoto, M.; Ohashi, W.; Hojyo, S.; Atsumi, T.; Ueda, N.; Azuma, I.; Hirota, H.; Murakami, M. Zinc suppresses Th17 development via inhibition of STAT3 activation. International immunology 2010, 22 (5), 375-386.
(48) Narimatsu, M.; Maeda, H.; Itoh, S.; Atsumi, T.; Ohtani, T.; Nishida, K.; Itoh, M.; Kamimura, D.; Park, S.-J.; Mizuno, K. Tissue-specific autoregulation of the stat3 gene and its role in interleukin-6-induced survival signals in T cells. Molecular and cellular biology 2001.
(49) Nish, S. A.; Schenten, D.; Wunderlich, F. T.; Pope, S. D.; Gao, Y.; Hoshi, N.; Yu, S.; Yan, X.; Lee, H. K.; Pasman, L. T cell-intrinsic role of IL-6 signaling in primary and memory responses. elife 2014, 3, e01949.
(50) Orange, S. T.; Leslie, J.; Ross, M.; Mann, D. A.; Wackerhage, H. The exercise IL-6 enigma in cancer. Trends in Endocrinology & Metabolism 2023.
(51) Fridman, W. H.; Pagès, F.; Sautès-Fridman, C.; Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nature Reviews Cancer 2012, 12 (4), 298-306.
(52) Tsukamoto, H.; Senju, S.; Matsumura, K.; Swain, S. L.; Nishimura, Y. IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nature communications 2015, 6 (1), 6702.
(53) Zelba, H.; Weide, B.; Martens, A.; Derhovanessian, E.; Bailur, J. K.; Kyzirakos, C.; Pflugfelder, A.; Eigentler, T. K.; Di Giacomo, A. M.; Maio, M. Circulating CD4+ T cells that produce IL4 or IL17 when stimulated by melan-A but not by NY-ESO-1 have negative impacts on survival of patients with stage IV melanoma. Clinical Cancer Research 2014, 20 (16), 4390-4399.
(54) La Gruta, N. L.; Gras, S.; Daley, S. R.; Thomas, P. G.; Rossjohn, J. Understanding the drivers of MHC restriction of T cell receptors. Nature Reviews Immunology 2018, 18 (7), 467-478.
(55) Joyce, J. A.; Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 2015, 348 (6230), 74-80.
(56) Luckheeram, R. V.; Zhou, R.; Verma, A. D.; Xia, B. CD4+ T cells: differentiation and functions. Journal of Immunology Research 2012, 2012 (1), 925135.
(57) Murray, H. W.; Rubin, B.; Carriero, S.; Harris, A.; Jaffee, E. Human mononuclear phagocyte antiprotozoal mechanisms: oxygen-dependent vs oxygen-independent activity against intracellular Toxoplasma gondii. Journal of immunology (Baltimore, Md.: 1950) 1985, 134 (3), 1982-1988.
(58) De Biasi, S.; Meschiari, M.; Gibellini, L.; Bellinazzi, C.; Borella, R.; Fidanza, L.; Gozzi, L.; Iannone, A.; Lo Tartaro, D.; Mattioli, M. Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia. Nature communications 2020, 11 (1), 3434.
(59) Jiang, Y.; Li, Y.; Zhu, B. T-cell exhaustion in the tumor microenvironment. Cell death & disease 2015, 6 (6), e1792-e1792.
(60) Barber, D. L.; Wherry, E. J.; Masopust, D.; Zhu, B.; Allison, J. P.; Sharpe, A. H.; Freeman, G. J.; Ahmed, R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006, 439 (7077), 682-687.
(61) Keegan, A.; Ricciuti, B.; Garden, P.; Cohen, L.; Nishihara, R.; Adeni, A.; Paweletz, C.; Supplee, J.; Jänne, P. A.; Severgnini, M. Plasma IL-6 changes correlate to PD-1 inhibitor responses in NSCLC. Journal for immunotherapy of cancer 2020, 8 (2).
(62) Shen, M. J.; Xu, L. J.; Yang, L.; Tsai, Y.; Keng, P. C.; Chen, Y.; Lee, S. O.; Chen, Y. Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. Oncotarget 2017, 8 (46), 80506.
(63) Yi, M.; Niu, M.; Xu, L.; Luo, S.; Wu, K. Regulation of PD-L1 expression in the tumor microenvironment. Journal of hematology & oncology 2021, 14, 1-13.
(64) Ziegler, S. F.; Ramsdell, F.; Hjerrild, K. A.; Armitage, R. J.; Grabstein, K. H.; Hennen, K. B.; Farrah, T.; Fanslow, W. C.; Shevach, E. M.; Alderson, M. R. Molecular characterization of the early activation antigen CD69: a type II membrane glycoprotein related to a family of natural killer cell activation antigens. European journal of immunology 1993, 23 (7), 1643-1648.
(65) de la Fuente, H.; Cruz-Adalia, A.; Martinez del Hoyo, G.; Cibrián-Vera, D.; Bonay, P.; Pérez-Hernández, D.; Vázquez, J.; Navarro, P.; Gutierrez-Gallego, R.; Ramirez-Huesca, M. The leukocyte activation receptor CD69 controls T cell differentiation through its interaction with galectin-1. Molecular and cellular biology 2014, 34 (13), 2479-2487.
(66) Kuo, P. T.; Zeng, Z.; Salim, N.; Mattarollo, S.; Wells, J. W.; Leggatt, G. R. The role of CXCR3 and its chemokine ligands in skin disease and cancer. Frontiers in medicine 2018, 5, 271.
(67) Groom, J. R.; Luster, A. D. CXCR3 in T cell function. Experimental cell research 2011, 317 (5), 620-631.
(68) Lilliebladh, S.; Johansson, Å.; Pettersson, Å.; Ohlsson, S.; Hellmark, T. Phenotypic Characterization of Circulating CD4+ T Cells in ANCA‐Associated Vasculitis. Journal of Immunology Research 2018, 2018 (1), 6984563.
(69) Zhang, J.; Liu, J.; Chen, H.; Wu, W.; Li, X.; Wu, Y.; Wang, Z.; Zhang, K.; Li, Y.; Weng, Y. Specific immunotherapy generates CD8+ CD196+ T cells to suppress lung cancer growth in mice. Immunologic research 2016, 64, 1033-1040.
(70) Chen, X.; Oppenheim, J. J. Th17 cells and Tregs: unlikely allies. Journal of leukocyte biology 2014, 95 (5), 723-731.
(71) Liu, J.; Chen, Z.; Li, Y.; Zhao, W.; Wu, J.; Zhang, Z. PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Frontiers in pharmacology 2021, 12, 731798.
(72) Riley, J. L. PD‐1 signaling in primary T cells. Immunological reviews 2009, 229 (1), 114-125.
(73) Daassi, D.; Mahoney, K. M.; Freeman, G. J. The importance of exosomal PDL1 in tumour immune evasion. Nature Reviews Immunology 2020, 20 (4), 209-215.
(74) Ke, W.; Zhang, L.; Dai, Y. The role of IL‐6 in immunotherapy of non‐small cell lung cancer (NSCLC) with immune‐related adverse events (irAEs). Thoracic cancer 2020, 11 (4), 835-839.
(75) Liu, C.; Yang, L.; Xu, H.; Zheng, S.; Wang, Z.; Wang, S.; Yang, Y.; Zhang, S.; Feng, X.; Sun, N. Correction: Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer. BMC medicine 2022, 20.
(76) Kak, G.; Raza, M.; Tiwari, B. K. Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases. Biomolecular concepts 2018, 9 (1), 64-79.
(77) Burke, J. D.; Young, H. A. IFN-γ: A cytokine at the right time, is in the right place. In Seminars in immunology, 2019; Elsevier: Vol. 43, p 101280.
(78) McLoughlin, R. M.; Witowski, J.; Robson, R. L.; Wilkinson, T. S.; Hurst, S. M.; Williams, A. S.; Williams, J. D.; Rose-John, S.; Jones, S. A.; Topley, N. Interplay between IFN-γ and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. The Journal of clinical investigation 2003, 112 (4), 598-607.
(79) Longbottom, E. R.; Torrance, H. D.; Owen, H. C.; Fragkou, P. C.; Hinds, C. J.; Pearse, R. M.; O’Dwyer, M. J. Features of postoperative immune suppression are reversible with interferon gamma and independent of interleukin-6 pathways. Annals of surgery 2016, 264 (2), 370-377.
(80) Holtmann, M. H.; Neurath, M. F. Differential TNF-signaling in chronic inflammatory disorders. Current molecular medicine 2004, 4 (4), 439-444.
(81) Liu, Y.; Gao, Y.; Lin, T. Expression of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) in non-small cell lung cancer and its relationship with the occurrence and prognosis of cancer pain. Annals of Palliative Medicine 2021, 10 (12), 127592766-127512766.
(82) Yang, J.; Zhang, C. Regulation of cancer‐immunity cycle and tumor microenvironment by nanobiomaterials to enhance tumor immunotherapy. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2020, 12 (4), e1612.
(83) Abbott, M.; Ustoyev, Y. Cancer and the immune system: the history and background of immunotherapy. In Seminars in oncology nursing, 2019; Elsevier: Vol. 35, p 150923.
(84) Grivennikov, S. I.; Greten, F. R.; Karin, M. Immunity, inflammation, and cancer. Cell 2010, 140 (6), 883-899.
(85) Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. nature 2008, 454 (7203), 436-444.
(86) Zarogoulidis, K.; Zarogoulidis, P.; Darwiche, K.; Boutsikou, E.; Machairiotis, N.; Tsakiridis, K.; Katsikogiannis, N.; Kougioumtzi, I.; Karapantzos, I.; Huang, H. Treatment of non-small cell lung cancer (NSCLC). Journal of thoracic disease 2013, 5 (Suppl 4), S389.
(87) Sardarabadi, P.; Kojabad, A. A.; Jafari, D.; Liu, C.-H. Liquid biopsy-based biosensors for MRD detection and treatment monitoring in Non-Small Cell Lung Cancer (NSCLC). Biosensors 2021, 11 (10), 394.
(88) Chytaieva, H.; Zakhartseva, L. PD-L1 expression in bronchopulmonary neuroendocrine tumors: correlation with morphological features and prognosis. 2021.
(89) Horvath, L.; Thienpont, B.; Zhao, L.; Wolf, D.; Pircher, A. Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC)-novel approaches and future outlook. Molecular Cancer 2020, 19, 1-15.
(90) Azizipour, N.; Avazpour, R.; Rosenzweig, D. H.; Sawan, M.; Ajji, A. Evolution of biochip technology: A review from lab-on-a-chip to organ-on-a-chip. Micromachines 2020, 11 (6), 599.
(91) Rolfo, C.; Caglevic, C.; Santarpia, M.; Araujo, A.; Giovannetti, E.; Gallardo, C. D.; Pauwels, P.; Mahave, M. Immunotherapy in NSCLC: a promising and revolutionary weapon. Immunotherapy 2017, 97-125.
(92) Freshney, R. I. Basic principles of cell culture. Wiley Online Library: 2006; pp 3-22.
(93) Kapałczyńska, M.; Kolenda, T.; Przybyła, W.; Zajączkowska, M.; Teresiak, A.; Filas, V.; Ibbs, M.; Bliźniak, R.; Łuczewski, Ł.; Lamperska, K. 2D and 3D cell cultures–a comparison of different types of cancer cell cultures. Archives of medical science 2018, 14 (4), 910-919.
(94) Fontoura, J. C.; Viezzer, C.; Dos Santos, F. G.; Ligabue, R. A.; Weinlich, R.; Puga, R. D.; Antonow, D.; Severino, P.; Bonorino, C. Comparison of 2D and 3D cell culture models for cell growth, gene expression and drug resistance. Materials Science and Engineering: C 2020, 107, 110264.
(95) Ravi, M.; Paramesh, V.; Kaviya, S.; Anuradha, E.; Solomon, F. P. 3D cell culture systems: advantages and applications. Journal of cellular physiology 2015, 230 (1), 16-26.
(96) Yamada, K. M.; Sixt, M. Mechanisms of 3D cell migration. Nature Reviews molecular cell biology 2019, 20 (12), 738-752.
(97) Joaquin, D.; Grigola, M.; Kwon, G.; Blasius, C.; Han, Y.; Perlitz, D.; Jiang, J.; Ziegler, Y.; Nardulli, A.; Hsia, K. J. Cell migration and organization in three‐dimensional in vitro culture driven by stiffness gradient. Biotechnology and bioengineering 2016, 113 (11), 2496-2506.
(98) de Groot, T. E. Open Microfluidic Platforms for Tissue Culture; The University of Wisconsin-Madison, 2016.
(99) Van Duinen, V.; Trietsch, S. J.; Joore, J.; Vulto, P.; Hankemeier, T. Microfluidic 3D cell culture: from tools to tissue models. Current opinion in biotechnology 2015, 35, 118-126.
(100) Essaouiba, A.; Okitsu, T.; Kinoshita, R.; Jellali, R.; Shinohara, M.; Danoy, M.; Legallais, C.; Sakai, Y.; Leclerc, E. Development of a pancreas-liver organ-on-chip coculture model for organ-to-organ interaction studies. Biochemical Engineering Journal 2020, 164, 107783.
(101) Yue, B. Biology of the extracellular matrix: an overview. Journal of glaucoma 2014, 23, S20-S23.
(102) Aldana, A. A.; Valente, F.; Dilley, R.; Doyle, B. Development of 3D bioprinted GelMA-alginate hydrogels with tunable mechanical properties. Bioprinting 2021, 21, e00105.
(103) Chen, Z.; Hu, X.; Lin, Z.; Mao, H.; Qiu, Z.; Xiang, K.; Ke, T.; Li, L.; Lu, L.; Xiao, L. Layered GelMA/PEGDA hydrogel microneedle patch as an intradermal delivery system for hypertrophic scar treatment. ACS Applied Materials & Interfaces 2023, 15 (37), 43309-43320.
(104) Chen, X.; Zhang, D.; Wang, X.; Liu, Z.; Kang, H.; Liu, C.; Chen, F. Preparation of porous GelMA microcarriers by microfluidic technology for Stem-Cell culture. Chemical Engineering Journal 2023, 477, 146444.
(105) Lee, Y.; Lee, J. M.; Bae, P. K.; Chung, I. Y.; Chung, B. H.; Chung, B. G. Photo‐crosslinkable hydrogel‐based 3D microfluidic culture device. Electrophoresis 2015, 36 (7-8), 994-1001.
(106) Sardarabadi, P.; Lee, K.-Y.; Sun, W.-L.; Kojabad, A. A.; Liu, C.-H. Investigating T Cell Immune Dynamics and IL-6’s Duality in a Microfluidic Lung Tumor Model. ACS Applied Materials & Interfaces 2024. DOI: 10.1021/acsami.4c09065.
(107) Sardarabadi, P.; Lee, K.-Y.; Sun, W.-L.; Liu, C.-H. Immune response to IL6 gradient in a diffusion-based microfluidic labchip. Sensors and Actuators B: Chemical 2024, 417, 136141.
(108) Lee, B.; Lee, S.-H.; Shin, K. Crosstalk between fibroblasts and T cells in immune networks. Frontiers in Immunology 2023, 13, 1103823.
(109) Cavagnero, K. J.; Gallo, R. L. Essential immune functions of fibroblasts in innate host defense. Frontiers in Immunology 2022, 13, 1058862.
(110) Karakasheva, T. A.; Lin, E. W.; Tang, Q.; Qiao, E.; Waldron, T. J.; Soni, M.; Klein-Szanto, A. J.; Sahu, V.; Basu, D.; Ohashi, S. IL-6 mediates cross-talk between tumor cells and activated fibroblasts in the tumor microenvironment. Cancer Research 2018, 78 (17), 4957-4970.
(111) Silva, E. M.; Mariano, V. S.; Pastrez, P. R. A.; Pinto, M. C.; Castro, A. G.; Syrjanen, K. J.; Longatto-Filho, A. High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer. PloS one 2017, 12 (7), e0181125.
(112) Yoshimatsu, Y.; Wakabayashi, I.; Kimuro, S.; Takahashi, N.; Takahashi, K.; Kobayashi, M.; Maishi, N.; Podyma‐Inoue, K. A.; Hida, K.; Miyazono, K. TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation. Cancer science 2020, 111 (7), 2385-2399.
(113) Nascimbeni, M.; Shin, E.-C.; Chiriboga, L.; Kleiner, D. E.; Rehermann, B. Peripheral CD4+ CD8+ T cells are differentiated effector memory cells with antiviral functions. Blood 2004, 104 (2), 478-486.
(114) Hagen, M.; Pangrazzi, L.; Rocamora-Reverte, L.; Weinberger, B. Legend or truth: Mature CD4+ CD8+ double-positive T cells in the periphery in health and disease. Biomedicines 2023, 11 (10), 2702.
(115) Schad, S. E.; Chow, A.; Mangarin, L.; Pan, H.; Zhang, J.; Ceglia, N.; Caushi, J. X.; Malandro, N.; Zappasodi, R.; Gigoux, M. Tumor-induced double positive T cells display distinct lineage commitment mechanisms and functions. Journal of Experimental Medicine 2022, 219 (6), e20212169.
(116) Cabrera-Rivera, G. L.; Madera-Sandoval, R. L.; León-Pedroza, J. I.; Ferat-Osorio, E.; Salazar-Rios, E.; Hernández-Aceves, J. A.; Guadarrama-Aranda, U.; López-Macías, C.; Wong-Baeza, I.; Arriaga-Pizano, L. A. Increased TNF-α production in response to IL-6 in patients with systemic inflammation without infection. Clinical and Experimental Immunology 2022, 209 (2), 225-235.
(117) Wherry, E. J.; Blattman, J. N.; Murali-Krishna, K.; Van Der Most, R.; Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. Journal of virology 2003, 77 (8), 4911-4927.
(118) Saito, H.; Kuroda, H.; Matsunaga, T.; Osaki, T.; Ikeguchi, M. Increased PD‐1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer. Journal of surgical oncology 2013, 107 (5), 517-522.
(119) Rodrigues, L. S.; Barreto, A. S.; Bomfim, L. G. S.; Gomes, M. C.; Ferreira, N. L. C.; da Cruz, G. S.; Magalhães, L. S.; de Jesus, A. R.; Palatnik-de-Sousa, C. B.; Corrêa, C. B. Multifunctional, TNF-α and IFN-γ-Secreting CD4 and CD8 T Cells and CD8High T Cells Are Associated With the Cure of Human Visceral Leishmania sis. Frontiers in Immunology 2021, 12, 773983.
(120) Pesce, B.; Ribeiro, C. H.; Larrondo, M.; Ramos, V.; Soto, L.; Catalán, D.; Aguillón, J. C. TNF-α affects signature cytokines of Th1 and Th17 T cell subsets through differential actions on TNFR1 and TNFR2. International Journal of Molecular Sciences 2022, 23 (16), 9306.
(121) Shrihari, T. Dual role of inflammatory mediators in cancer. Ecancermedicalscience 2017, 11.
(122) Ozga, A. J.; Chow, M. T.; Luster, A. D. Chemokines and the immune response to cancer. Immunity 2021, 54 (5), 859-874.
(123) Yamaji, H.; Iizasa, T.; Koh, E.; Suzuki, M.; Otsuji, M.; Chang, H.; Motohashi, S.; Yokoi, S.; Hiroshima, K.; Tagawa, M. Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer. Cancer Immunology, Immunotherapy 2004, 53, 786-792.
(124) Dienz, O.; Rincon, M. The effects of IL-6 on CD4 T cell responses. Clinical immunology 2009, 130 (1), 27-33.
(125) Hirano, T. IL-6 in inflammation, autoimmunity and cancer. International immunology 2021, 33 (3), 127-148.
(126) Rašková, M.; Lacina, L.; Kejík, Z.; Venhauerová, A.; Skaličková, M.; Kolář, M.; Jakubek, M.; Rosel, D.; Smetana Jr, K.; Brábek, J. The role of IL-6 in cancer cell invasiveness and metastasis—overview and therapeutic opportunities. Cells 2022, 11 (22), 3698.
(127) Lastwika, K. J. Regulation and Consequences of PD-L1 Expression in Non-Small Cell Lung Cancer. The George Washington University, 2014.
(128) Munir, S.; Lundsager, M. T.; Jørgensen, M. A.; Hansen, M.; Petersen, T. H.; Bonefeld, C. M.; Friese, C.; Met, Ö.; thor Straten, P.; Andersen, M. H. Inflammation induced PD-L1-specific T cells. Cell Stress 2019, 3 (10), 319.
(129) Thommen, D. S.; Koelzer, V. H.; Herzig, P.; Roller, A.; Trefny, M.; Dimeloe, S.; Kiialainen, A.; Hanhart, J.; Schill, C.; Hess, C. 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. Nature medicine 2018, 24 (7), 994-1004.
(130) MINUTI, G. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. 2014.
(131) Wang, M.-J.; Zhang, H.-L.; Chen, F.; Guo, X.-J.; Liu, Q.-G.; Hou, J. The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases. Experimental Hematology & Oncology 2024, 13 (1), 62.

簡易檢索 / 詳目顯示

相關論文