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The Role of Human Leukocyte Antigen-G and Its Polymorphisms in Post-Transplant Malignancy and Acute Rejection Following Heart Transplantation

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The Role of Human Leukocyte Antigen-G and Its Polymorphisms in Post-Transplant Malignancy and Acute Rejection Following Heart Transplantation The Role of Human Leukocyte Antigen-G and its Polymorphisms in Post-transplant Malignancy and Acute Rejection Following Heart Transplantation by Mitchell B. Adamson A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Mitchell B. Adamson, 2019 The Role of Human Leukocyte Antigen-G and its Polymorphisms in Post-transplant Malignancy and Acute Rejection Following Heart Transplantation Mitchell B. Adamson, BSc. Master of Science Institute of Medical Science University of Toronto 2019 Abstract Human leukocyte antigen-G (HLA-G) has shown to increase cancer risk but reduce rejection post-transplant by dampening the immune response. Cancerous cells may utilize HLA-G as a mechanism to evade the immune response. HLA-G expression is mediated by genetic polymorphisms, however their association with post-transplant outcomes remains elusive. The objective was to evaluate HLA-G donor-recipient polymorphism matching and development of cancer/rejection following heart transplantation. Recipients (n=251) and donors (n=196) were genotyped to identify HLA-G polymorphisms in the coding, 5’regulatory and 3’untranslated regions. Association between outcomes and polymorphism matching was assessed via cox regression. Overall, 17% of recipients were diagnosed with cancer post-transplant. Donor- recipient 14BP polymorphism matching reduced the proportion of cancer and was independently protective against cancer development (HR[95%CI]: 0.26 [0.10-0.75], p=0.012). HLA-G may have a role in targeted therapeutic and diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy in order to reduce cancer risk post-transplant. ii Acknowledgments The completion of this thesis would not have been possible without the help and support of many wonderful supervisors, colleagues and friends. Without their help and guidance, none of this work would have been possible. I would like to start by saying thank you to my supervisor, Dr. Vivek Rao, for taking me on as your Master’s Student. Your continued guidance and helpful advice helped me excel throughout my graduate degree. I am especially grateful to my co-supervisor Dr. Diego Delgado. Thank you for acting as a mentor and providing the opportunity to expand myself as a researcher. I am forever grateful for your scientific and personal advice. I am grateful for my mentors and have learned an enormous deal from both of you in terms of being a clinician-scientist. I would like to thank my program advisory committee members, Dr. Stephen Juvet and Dr. Dinesh Thavendiranathan. Your insight and valuable suggestions have helped me think critically, reflect upon ideas and expand my knowledge far beyond my project. To the Rao lab and colleagues, thank you for making my time here enjoyable and memorable. To Frank, thanks for all of your help and for always making things fun and entertaining. To Ved, your continued support helped me throughout my degree; thanks for always listening and providing advice. You both have made my time here unforgettable. I would also like to extend my sincerest thanks to Julieta Lazarte. This project would not have been possible without your ideas and guidance. Thank you to all for supporting my research and providing career advice. A special thanks to Dr. Roberto Ribeiro for acting as a role model, both in my academic and personal life. Your ongoing lessons and advice helped me thrive, and revealed my true potential as a researcher. Aside from all of your contributions to my project, thank you for teaching me and being a great friend over the years; the laughs and memories will not be forgotten. Finally, I would like to thank all of my friends, my parents, Michele and Alastair, my sister Jillian, and my girlfriend Laura for their love and unwavering support throughout my life and schooling. Your encouragement and continuous support helped push me through both the good times and bad and kept me motivated throughout my graduate degree. iii Statement of Contributions I would also like to thank the following for their contributions to my project: First and foremost to the Rao lab for all of your help throughout the course of the project. Roberto, for your help with project ideas, statistics and reviewing; Frank for all of your help with the HLA-G database and its analysis; and Ved for your insight and revisions to the project. The HLA laboratory and staff, including Dr. Kathryn Tinckam for helping me acquire DNA samples and blood samples from donors and recipients. This work would not have been possible without your help Swan Cot from the Clinical Genomics Centre: for your help identifying polymorphisms and genotyping samples. Kyle Runeckles and Dr. Manlhiot for your great help in statistical analysis. None of the work would have been possible without your insight and ideas. Kyle, aside from my project you have taken my statistical knowledge to a higher level, and for that I thank you. To my committee members, Dr. Juvet and Dr. Thavendiranathan, thank you for your support and guidance in my project. Your ideas and helpful criticism helped expand my work to the next level. Also, a big thank you to Dr. Phyllis Billia and her laboratory for their support and critical appraisal of my project. Thank you for providing me an informal setting to showcase my work and gain valued feedback. Finally, to Dr. Rao and Dr. Delgado for their consistent guidance throughout my project. Thank you for all of the help with project conception, revisions and submissions that I have made throughout my Master’s degree. iv Table of Contents ACKNOWLEDGMENTS III STATEMENT OF CONTRIBUTIONS IV TABLE OF CONTENTS V LIST OF TABLES X LIST OF FIGURES XII LIST OF APPENDICES XIV CHAPTER 1 LITERATURE REVIEW 1 INTRODUCTION 1 1.1 Overview 1 1.2 Transplantation and Immunology Background 2 1.2.1 Heart Transplantation 2 1.2.2 Risk Factors and Post-Transplantation Complications 3 1.2.2.1 Acute Rejection 4 1.2.2.2 Post-transplantation Cancer 6 1.2.3 Innate and Adaptive Immune System 7 1.2.4 The Major Histocompatibility Complex and Allorecognition 8 1.2.5 Other Non-classical HLA Molecules 10 1.3 Human Leukocyte Antigen-G 12 1.3.1 HLA-G Overview 12 1.3.2 HLA-G Expression 13 1.3.3 HLA-G Genetic Structure 15 v 1.3.4 HLA-G as an Immune Checkpoint 22 1.3.5 HLA-G Receptors 23 1.3.6 HLA-G Mechanisms of immune modulation 27 1.3.6.1 Direct and Indirect Mechanisms of HLA-G 27 1.3.6.2 Non-immune functions of HLA-G 31 1.3.7 Other Non-classical HLA molecules 32 1.4 HLA-G Polymorphisms 32 1.4.1 Polymorphism Overview and Nomenclature 32 1.4.2 HLA-G Coding Region Variability and Haplotypes 34 1.4.2.1 Haplotype II 36 1.4.2.2 Haplotype III 36 1.4.2.3 Haplotype IV 37 1.4.2.4 Haplotype V 38 1.4.2.5 Haplotype VI 38 1.4.3 HLA-G 5’ Upstream Regulatory Region Variability 38 1.4.3.1 Single Nucleotide Polymorphism: –725 G/C/T 42 1.4.3.2 Single Nucleotide Polymorphism: –201 G/A 43 1.4.4 HLA-G 3’ Untranslated Region Variability 44 1.4.4.1 The 14-Base Pair Indel Polymorphism 47 1.4.4.2 Single Nucleotide Polymorphism: +3142 C/G 48 1.4.4.3 Single Nucleotide Polymorphism: +3187 A/G 49 1.4.4.4 Single Nucleotide Polymorphism: +3196 C/G 49 1.4.5 HLA-G Extended Haplotypes 50 1.5 HLA-G in the Clinical Setting 52 1.5.1 HLA-G in Pregnancy 52 1.5.2 The Role of HLA-G in Transplantation and Rejection 53 1.5.2.1 Heart Transplantation 53 1.5.2.2 HLA-G in other Solid Organ Transplants 55 1.5.2.3 The Role of the Donor HLA-G Genotype 57 1.5.3 The Role of HLA-G in Cancer 58 vi 1.5.3.1 HLA-G Influences Cancer Outcomes 58 1.5.3.2 HLA-G and its Mechanism in Cancer Progression 60 1.5.3.3 HLA-G Polymorphisms and Cancer 66 CHAPTER 2 AIMS AND HYPOTHESIS 68 THE ROLE OF DONOR AND RECIPIENT HLA-G POLYMORPHISMS IN POST- TRANSPLANT CANCER AND ACUTE REJECTION 68 2.1 Summary and Rationale 68 CHAPTER 3 METHODS 71 STUDY DESIGN 71 3.1 Population of Interest 71 3.1.1 Patients 71 3.2 Outcomes of Interest 72 3.2.1 Cancer Screening 72 3.2.2 Acute Rejection Screening 73 3.2.3 General Post-Transplantation Outcomes 74 3.3 Blood/DNA Collection 75 3.3.1 Blood Collection 75 3.3.2 DNA Extraction 75 3.4 Polymorphisms 76 3.4.1 Overview of Polymorphism Selection 76 3.4.2 Polymorphism Genotyping 77 3.5 Statistical Analysis 79 CHAPTER 4 RESULTS 82 vii HLA-G POLYMORPHISMS AND THEIR INFLUENCE ON POST-TRANSPLANT CANCER AND ACUTE REJECTION 82 4.1 Recipient and Donor Pre-Transplantation Characteristics 82 4.2 Post-Transplant Characteristics, Clinical Outcomes and Therapy 85 4.2.1 Post Transplantation Characteristics and Medical Therapy 85 4.2.2 Post-Transplant Cancer Clinical Outcomes 89 4.2.3 Acute Rejection Clinical Outcomes 92 4.3 Polymorphism Outcomes 94 4.4 Predictors of Post-Transplant Malignancy 98 4.4.1 Recipient/Donor 14-bp Polymorphism Matching is Protective Against Development of Post-transplantation Cancer 104 4.4.2 Recipient/donor +3196 GC-GC Matching and its Influence on Post-transplant Cancer 113 4.5 Predictors of Acute Rejection 115 CHAPTER 5 GENERAL DISCUSSION 123 GENERAL DISCUSSION 123 5.1 General Project Overview 123 5.2 HLA-G Polymorphisms Influence Post-transplant Cancer 124 5.3 The Mechanism of Donor-Recipient 14-bp Matching in Cancer 130 5.4 HLA-G Polymorphisms and their Influence on Acute Rejection 137 5.5 Clinical Implications 142 5.5.1 Translation and Relevance 142 5.5.2 HLA-G as a Biomarker 143 viii CHAPTER 6 LIMITATIONS AND FUTURE DIRECTIONS 145 LIMITATIONS AND FUTURE DIRECTIONS 145 CHAPTER 7 CONCLUSIONS 150 CONCLUSIONS 150 REFERENCES 151 APPENDICES 170 ix List of Tables Page Table 1 : Recipient and donor descriptive characteristics prior to heart 82 transplantation Table 2 : Recipient pre-transplant characteristics 84 Table 3 : Recipient post-operative characteristics and medical therapies utilized 86 Table 4 : Outcome characteristics for post-transplant cancer 90 Table 5: Outcome characteristics for post-transplant acute rejection 92 Table 6: Description of recipient HLA-G polymorphisms.
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