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研究生： 李欣學
Li, Sin-Syue
論文名稱： 抗PD-L1抗體透過破壞PD-L1/CD80同側異源雙合體減少活化嵌合抗原受體T細胞之存活率
Anti-PD-L1 antibody limits the survival of activated CAR T cells by disrupting the PD-L1 / CD80 cis-heterodimer
指導教授： 陳彩雲
Chen, Tsai-Yun
張孔昭
Chang, Kung-Chao
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2025
畢業學年度： 113
語文別： 英文
論文頁數： 101
中文關鍵詞： 嵌合抗原受體 、T細胞 、免疫檢查點抑制劑
外文關鍵詞： chimeric antigen receptor - CAR, T cell, immune checkpoint inhibitors
相關次數： 點閱：11  下載：0 
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    • Abstract ii 摘要 iii ACKNOWLEDGEMENTS iv TABLE OF CONTENTS v LIST OF TABLES viii LIST OF FIGURES ix LIST OF SYMBOLS AND ABBREVIATIONS xi CHAPTER 1 INTRODUCTION 1 1.1 The emergence of CAR T cell therapy in cancer treatment 1 1.1.1 Early development of CAR T therapy 1 1.1.2 Clinical approval and application of CD19 CAR T cell therapy 2 1.2 Limitations of CAR T cell therapy 2 1.2.1 Antigen escape 3 1.2.2 Limited persistence and T cell exhaustion 3 1.2.3 Immunosuppressive microenvironment 5 1.2.4 The CAR and the TRUCK 6 1.3 PD‑L1/PD-1 immune checkpoints and CAR T cells 7 1.3.1 PD-1-mediated immunosuppression 7 1.3.2 CAR engineering strategies to overcome PD‑L1/PD-1-mediated suppression 8 1.4 Knowns and unknowns of combining PD‑L1 blockade with CAR T cells 9 1.4.1 PD‑L1 as a target for cancer immunotherapy 9 1.4.2 Combination of anti-PD‑L1 antibody and CD19 CAR T 10 1.4.3 Rationale of this study 11 CHAPTER 2 Material and Methods 13 2.1 Cells and culture conditions 13 2.2 Design of CAR constructs with co-expression of anti-PD‑L1 antibody fragment 14 2.3 Antibodies used in functional assays 14 2.4 Flow cytometry 15 2.5 Production of retrovirus by co-transfection 16 2.6 Activation, retroviral transduction, and enrichment of CAR T cells 16 2.7 Repetitive stimulation assay 17 2.8 Apoptosis detection assays 17 2.9 Structural mapping of protein-protein interactions 18 2.10 Proximity ligation assay 18 2.11 Jurkat reporter cell line assay 19 2.12 Statistical analysis 19 CHAPTER 3 Results 21 3.1 Generation of CAR T cells with secretion of anti-PD‑L1 antibody fragments 21 3.2 Continuous secretion of anti-PD-L1 scFv may compromise CAR T cell expansion under repeated antigen exposure 22 3.3 CAR T cells co-expressing anti-PD‑L1 scFv display features of T cell exhaustion 23 3.4 CAR T cells secreting anti-PD-L1 scFv exhibit enhanced activation-induced apoptosis 23 3.5 Blockade of PD‑L1 on activated CAR T cells induces enhanced apoptosis 24 3.6 Anti-PD-L1 antibody disrupts the PD-L1/CD80 cis-interaction 25 3.7 PD-L1 blockade during CAR T activation results in diminished CD80 expression 26 3.8 CTLA-4 blockade restores CD80 expression and attenuates atezolizumab-induced apoptosis 27 3.9 PD-L1 blockade also reduces CD80 and TCR signaling in non-CAR T cells 28 3.10 Mechanistic summary based on experimental findings 28 CHAPTER 4 Discussion and Conclusion 31 4.1 Complexity of PD‑L1-mediated regulation in the tumor microenvironment 31 4.2 Functional implications of PD-L1/CD80 cis-interactions in CAR T Cells 32 4.3 CTLA-4-mediated depletion of CD80 drives apoptosis after PD-L1 blockade 32 4.4 Considerations of PD-L1 “back-signaling” and antibody specificity 33 4.5 Clinical impact of this study 34 4.6 Future perspectives 34 4.7 Conclusion 35 CHAPTER 5 References 37 Appendix A Tables 53 Appendix B Figures 55

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