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The Molecular Determinants of Tumor Cell Modulation Of THE MOLECULAR DETERMINANTS OF TUMOR CELL MODULATION OF IMMUNE SELECTION A Dissertation Submitted to the Faculty of the Graduate School of Arts and Sciences Of Georgetown University In partial fulfillment of the requirements for the Degree of Doctor of Philosophy In Tumor Biology By Casey Weber Shuptrine, M.E. Washington, DC June 9, 2015 Copyright © 2015 by Casey Weber Shuptrine All Rights Reserved ii The Molecular Determinants of Tumor Cell Modulation of Immune Rejection Casey Weber Shuptrine, M.E. Dissertation Advisor: Louis M. Weiner, M.D. ABSTRACT Over the past century, the identification of molecules that tumor cells utilize to manipulate the activation or survival of immune cells has proven difficult. Expression analyses have helped to discover the downregulation of PD-L1, TGF- β, and FasL in the tumor microenvironment. Mutation analyses have helped identify novel tumor-specific or –associated antigens presented to the cell surface through major histocompatibility (MHC) complexes. Unfortunately, these techniques often fail to recognize the complex cross-talk occurring between cells in the tumor microenvironment to influence the anti- cancer immune response. By employing an RNAi screen in vivo, we have parsed how gene knockdown in tumor cells affects the ability of the immune system to identify and eliminate malignant cells. To identify tumor cell derived immune modulators, the EO771 breast adenocarcinoma cell line derived from a C57Bl/6 mice was transduced via lentiviral vectors with a barcoded genome-wide murine shRNA library and engrafted in immune-competent and immune-deficient mice. By analyzing the relative shRNA representation in tumors grown in the presence of a functional adaptive immune system compared to those grown in immune-deficient mice, we discovered a subset of tumor- based genes whose knock-down affects immune recognition. Pathway analysis identified enrichment of shRNAs targeting previously identified immune regulators, including the iii TGF-βR pathway and MHC class I antigen processing. By engrafting shRNA tumor cell lines targeting gene candidates in immune-competent and –deficient mice, we identified that CD47, Tex9, Pex14, and Sgpl1 play putative roles in T cell-dependent recognition and elimination of EO771 tumors. CD47, a known inhibitor of target cell phagocytosis by macrophages, also regulated the adaptive immune response. Two previously understudied molecules, Pex14 and Sgpl1, appear to have immune inhibitory functions, as their respective knockdown suppressed EO771 tumor growth and increased survival of immunocompetent mice. Tex9 serves as a potential tumor antigen or immune stimulant, as reduction of expression enhances tumor growth when EO771 tumors are grown in immunocompetent mice. Therefore, this functional in vivo screening approach enabled the discovery of CD47, Pex14, Sgpl1, and Tex9 as novel tumor-based modulators of anti- tumor adaptive immunity. To the best of our knowledge, we are the first to report the successful utilization of an in vivo functional genomics approach to identify novel tumor- based mediators of immune regulation. INDEX WORDS: RNAi, Functional screening, Genome-wide, shRNA, Immune editing, In Vivo Screen iv Dedication I dedicate this work first to my family. To my wife, Sam: Without you this wouldn’t have been possible. It is because of you that I have pushed myself to become the man and scientist that I am today. For this words are not enough, but for now, they will do. Thank you. To my father and mother, John and Kelly: Your love, support, and encouragement have motivated me beyond compare. Everything I have done and will do is a testament to the quality of your parenting. To my brother, Chris: Thank you for always being my best friend. Thank you for setting the bar high and showing me the importance of thinking critically. To the friends and extended family that have helped along the way. Thank you for letting me be a part of our community. And finally, this work is dedicated to all those who have been touched by cancer. It is for you that I work every day. v ACKNOWLEDGMENTS With humble gratitude, I would like to recognize my research advisor, Dr. Louis M. Weiner, for his support and guidance. By giving me the freedom to explore my own scientific inquiries with continuous advice and thoughtful criticism, you have instilled upon me a level of independence and confidence I would not have thought possible. I would like to thank Dr. Anton Wellstein, my committee chair, for having an inquisitive mind. It was your words that convinced me to join Georgetown’s tumor biology program for my PhD. So without you, this would not have been possible. I would also like to thank Drs. Michael Johnson, a committee member, and Anna Riegel, the tumor biology program director, for their personal guidance and for their crucial roles in the tumor biology program. Your never-ending desire to improve the quality of research and life in our program has helped make it what it is today. I would like to thank all of the remaining members of my thesis committee, Drs. Carolyn Hurley and Suzanne Ostrand-Rosenberg. Your guidance and advice were essential for the completion of this work. I sincerely appreciate all of the members of the Weiner lab who I have had the pleasure of working with. I thank Drs. Sandra Jablonski, Shangzi Wang, Yong Tang, Yongwei Zhang, and Wei Xu for your expert counsel. Special thanks to all of the graduate students in the lab: Joseph Murray, Dalal Aldegaither, Rochelle Nasto, Rishi Surana, and Marsha Salcie-Gautreaux. I am forever grateful to have shared with you the graduate experience. Without you all, I would not have had as rich of an education. vi I would also like to thank all members of the tumor biology training program and members of Lombardi Comprehensive Cancer Center for their advice and support. Special thanks to Dr. Karen Creswell in the Flow Cytometry & Cell Sorting Shared Resource for her limitless expertise and effort. I would also like to thank Xiaojun Zou in the Genomics and Epigenomics Shared Resource for her assistance. vii TABLE OF CONTENTS Chapter 1 ......................................................................................................................... 1 1.1 Introduction ................................................................................................... 1 1.2 Immune Editing Theory ................................................................................ 1 1.3 Immune Modulatory Key Players ................................................................. 3 1.4 Immunotherapy .............................................................................................. 8 1.5 Tumor Vaccines ........................................................................................... 10 1.6 Screening Methods ...................................................................................... 12 1.7 Conclusion ................................................................................................... 14 1.8 Bibliography ................................................................................................ 16 Chapter 2. Monoclonal Antibodies for the Treatment of Cancer .................................. 19 2.1 Abstract ........................................................................................................ 20 2.2 Introduction ................................................................................................. 20 2.3 Structure ....................................................................................................... 21 2.4 Mechanisms of Action .................................................................................. 22 2.5 Targeting Immune Cells ............................................................................... 29 2.6 Targeting the Tumor Microenvironment ..................................................... 32 2.7 Targeting Solid Tumors ................................................................................ 34 2.8 Combination Approaches ............................................................................ 38 2.9 Mechanisms of Resistance to Antibody Therapy ........................................ 42 2.10 Conclusion ................................................................................................. 46 2.11 Bibliography .............................................................................................. 47 2.12 Primary Figures .......................................................................................... 68 viii Chapter 3. Bifunctional Antibodies: Preclinical and Clinical Applications ................... 70 3.1 Abstract ........................................................................................................ 71 3.2 Introduction ................................................................................................. 72 3.3 First Generation bsAbs ................................................................................ 73 3.4 Triomabs ....................................................................................................... 79 3.5 Alternative Full-Length bsAbs .................................................................... 86 3.6 Recombinant Bispecific Antibodies ............................................................. 89 3.7 Bispecific T-Cell Engagers .......................................................................... 94 3.8 Imaging .....................................................................................................
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