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Characterization of the Effects of Sex and Estrogen Receptor Signaling on Antigen-Specific T Cells for Immunotherapy

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Characterization of the Effects of Sex and Estrogen Receptor Signaling on Antigen-Specific T Cells for Immunotherapy Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 2019 Characterization of the Effects of Sex and Estrogen Receptor Signaling on Antigen-Specific T Cells for Immunotherapy Flor Cecilia Navarro Negredo Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Biochemistry Commons Recommended Citation Navarro Negredo, Flor Cecilia, "Characterization of the Effects of Sex and Estrogen Receptor Signaling on Antigen-Specific T Cells for Immunotherapy" (2019). Dissertations. 3359. https://ecommons.luc.edu/luc_diss/3359 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 2019 Flor Cecilia Navarro Negredo LOYOLA UNIVERSITY CHICAGO CHARACTERIZATION OF THE EFFECTS OF SEX AND ESTROGEN RECEPTOR SIGNALING ON ANTIGEN-SPECIFIC T CELLS FOR IMMUNOTHERAPY A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN BIOCHEMISTRY AND MOLECULAR BIOLOGY BY FLOR C. NAVARRO NEGREDO CHICAGO, IL AUGUST 2019 ACKNOWLEDGEMENTS I would like to thank all of the people who made this dissertation possible. Dr. Stephanie K. Watkins, I would like to thank you for providing me the opportunity and resources to conduct my dissertation project in pursuit of the degree of Doctor of Philosophy. Your patience, abundant knowledge, and mentorship throughout my graduate degree have been invaluable to me. With your mentorship, I have become very familiar with a wide range of approaches to study tumor immunology. To my committee, chaired by Clodia Osipo Ph.D., and composed of José A. Guevara-Patiño, MD, Ph.D., Isabelle Caroline Le Poole, Ph.D., and Chrystal Paulos, Ph.D., thank you for your continuous support, thoughtful discussion, and willingness to help this project. I would like to further thank Clodia Osipo, Ph.D. for greatly supporting my research project as my committee chair. Her encouragement, constructive criticism, and patience made all the difference through the process of completing this project. I would also like to thank my graduate program director, Mitch Denning, Ph.D., who always inquired after my project and provided thoughtful comments and experienced recommendations. Further, I wish to thank everyone who assisted me and taught me critical techniques through my project. Most notably, I wish to thank Matthew Thompson, Ph.D., Kelly Barrios, Ph.D., Farshid Azarafrooz, D.V.M, Patricia Simms, Gina Scurti, Tamson Moore, Ph.D., and Annika Dalheim. I would also like to extend my gratitude to everyone that has previously worked in the laboratory of Stephanie K. Watkins including Lauren Nowak, Natalie Sweeney, Dan Peiffer, and Caroline Herrnreiter. iii I would like to thank Loyola University Chicago and the Biochemistry and Molecular Biology department for providing me with the opportunity and education needed to pursue this degree. The support of such an excellent institution has offered me limitless learning experiences that will help me become an independent scientist. Additionally, I would like to thank the American Cancer Society for awarding Dr. Stephanie K. Watkins with the ACS Research Scholar Grant RSG-16-242-01 which funded my project and allowed me to attend and present my findings in national and international conferences in Chicago, IL, Seattle, WA, Whistler, BC, Breckenridge, CO, and Boston, MA. I would like to thank all of my friends in the Cancer Center and other departments who have supported me and from whom I have learned so much. Whichever future career you all choose, I am sure you will succeed, if you have not already done so. To Jennifer Schreiber, Lulu Plaza-Rojas, Dave Ford, Joseph Cannova, Ph.D., Annie Roessler Ph.D., Tom Lynch, Ph.D., Jonathan Eby, Jeffrey Bloodworth, M.S and many others, thank you for your support, scientific feedback, and friendship. Lastly, I could not have completed this degree without the most important people in my life, my family and boyfriend, who supported me and encouraged me throughout the whole process. Thanks to my mother and father, Adela and Fernando, for providing me the opportunity of an advanced education. I thank my older sister Paloma who has always been an excellent role model to me and has helped me whenever I needed it. Special thanks to my cousin and best friend, Isa, who brings me joy every day. Thanks to my boyfriend, Peter, for his constant encouragement, support, and willingness to listen to my problems and for cheering me up whenever I most needed it. Finally, I would also like to thank Cookie for her unconditional love. Countless other friends, family, colleagues, and mentors over the years have all made an impact on my educational training and my life, and it has not gone without notice. Thank you. iv To my friends and family Not all those who wander are lost. J.R.R. Tolkien TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................................ iii LIST OF TABLES ........................................................................................................................... x LIST OF FIGURES ........................................................................................................................ xi LIST OF ABREVIATIONS ......................................................................................................... xiv ABSTRACT ................................................................................................................................... xx CHAPTER I: LITERATURE REVIEW ..........................................................................................1 Immunotherapy........................................................................................................................................ 1 T cell Signaling and Function................................................................................................................ 2 Types of Immunotherapy ....................................................................................................................... 6 Immune Checkpoint Blockade .......................................................................................................... 6 Adoptive T cell Transfer Immunotherapy ....................................................................................... 9 Immune Escape ..................................................................................................................................... 13 Sexual Dimorphism in Immune Responses: The role of Estrogen ................................................ 16 Sources of Estrogen .............................................................................................................................. 17 Estrogen Receptors (ERs) .................................................................................................................... 19 Structure of Estrogen Receptors .......................................................................................................... 20 Estrogen Receptor Signaling ............................................................................................................... 22 Ligand-Dependent Estrogen Signaling .......................................................................................... 22 The classical pathway: the ERE-dependent genomic pathway (Figure 3A). ........................... 22 The ERE-independent genomic pathway (Figure 3B) ............................................................. 24 Ligand-independent estrogen signaling (Figure 3C) .................................................................... 25 Non-genomic membrane bound estrogen signaling (Figure 3D) ............................................... 25 Estrogen Effect on Key Cells of the Immune System ...................................................................... 26 T cells & T cell cytokines ................................................................................................................ 26 B cells and antibody production...................................................................................................... 33 Macrophages and dendritic cells ..................................................................................................... 34 NK cells .............................................................................................................................................. 35 Estrogen and Disease ............................................................................................................................ 36 Estrogen and autoimmunity ............................................................................................................. 37 Estrogen and infection ...................................................................................................................... 38 Estrogen and cancer .......................................................................................................................... 39 Hepatocellular Carcinoma.................................................................................................................... 42 Causes ................................................................................................................................................
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