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Scholar Commons @USF University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School April 2019 Enhancing Immunotherapeutic Interventions for Treatment of Chronic Lymphocytic Leukemia Kamira K. Maharaj University of South Florida, [email protected] Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the Biology Commons, Cell Biology Commons, and the Immunology and Infectious Disease Commons Scholar Commons Citation Maharaj, Kamira K., "Enhancing Immunotherapeutic Interventions for Treatment of Chronic Lymphocytic Leukemia" (2019). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/8385 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Enhancing Immunomodulatory Therapeutic Interventions for Chronic Lymphocytic Leukemia by Kamira K. Maharaj A dissertation submitted in partial fulfillment Of the requirements for the degree of Doctor of Philosophy Department of Cancer Biology College of Arts and Sciences University of South Florida Major Professor: Javier Pinilla-Ibarz, M.D., Ph.D. Jose Conejo-Garcia, M.D., Ph.D. Sheng Wei, M.D. P.K. Epling-Burnette, Ph.D., Pharm.D. Shari Pilon-Thomas, Ph.D. John Pagel, M.D. Date of Approval: February 6, 2019 Keywords: HDAC, CLL, T cell, B cell, immune, ibrutinib Copyright © 2019, Kamira K. Maharaj DEDICATION I would like to dedicate this dissertation first and foremost to my family, who have tirelessly supported me in the pursuit of education. To both of my grandmothers, who believed in the power of education for their daughters and granddaughters. This work has been possible because I stand upon the shoulders of those who came before me. To my parents, Sataish and Kamla Maharaj, who have always believed in me while I followed my dreams. To my sister, Satira, who is my role model personally and professionally. To my eXtended family, especially Ravi, Alicia, Maya and Milan, who have been with me every step of the way. On another note, I dedicate this work to all the biomedical researchers who have come before me and those who will come after. Last but not least, I dedicate this work to all people who have experienced cancer. May you find strength to persevere. ACKNOWLEDGMENTS Firstly, I would like to acknowledge my extraordinary mentor, Dr. Javier Pinilla-Ibarz, for being the best mentor I could ask for during this process. I have learned so much from you. I am truly thankful to have had the incredible opportunity to train in your laboratory. Your influence has been the most instrumental in grooming my career. Thank you for your steady guidance, unwavering support on all fronts and for sharing your passion and expertise with me. Your patience, can-do attitude and tremendously exuberant personality have left a lasting imprint. I would like to acknowledge the other members of my committee for their support over the years. Drs. Burnette, Pilon-Thomas, Wei, and Conejo-Garcia, thank you for listening and providing feedback to shape my projects. Your perspectives have been extremely helpful. I also acknowledge Dr. Sotomayor who was my co-mentor for a brief time and who continued to provide feedback and champion our work. I eXtend my sincerest appreciation to Dr. John Pagel- a distinguished scientist and clinician- for giving your time to chair my defense. To our collaborators- it has been an exciting journey working together. I acknowledge the members of the Pinilla lab, past and present, with whom I have trained, worked, traveled to conferences, and coauthored manuscripts. Over the years, we have become a family, and this work is close to their hearts as it is to mine. A special thank you to Dr. Eva Sahakian, for the one-on-one training and mentoring. You have inspired me as a scientist and as a woman. Thank you for going above and beyond to share your knowledge and teach me life lessons. Most importantly, thank you for teaching me tenacity in the face of challenges. John Powers, thank you for sharing your technical expertise, and more importantly, your terrible dad jokes. You definitely helped my eXperiments “flow” more smoothly. Alex Achille, thank you for being my most fun colleague. I’ve lived my best lab life during our Friday 80’s dance parties. Susan Deng, Mibel Pabon-Saldana, Andressa Laino, Jie Chen, Renee Fonseca, Adrian Nieto, I am grateful to call you not only my colleagues but my friends. Thank you to our favorite lab-neighbors: Villagra lab, Shain lab and Betts lab. Dr. Brayer, Dr. Betts, Patricio Villaroel and Maritza Lienlaf-Moreno have provided great talks and excellent technical advice. I must also acknowledge the research specialists at Moffitt who have been instrumental in providing technical support for my projects- Tricia Watson in the vivarium, John Robinson and Jodi Kroger in the flow cytometry Core. Next, I extend my heartfelt gratitude to the USF/Moffitt Cancer Biology PhD program. Dr. Wright, thank you for the guidance throughout the years. The work you put into the Program is greatly appreciated by all of us who have passed through it. I also acknowledge the Moffitt faculty members who lectured us throughout our coursework, sharing their knowledge and helping us to understand difficult topics. As Dr. Monteiro infamously said during my first year, ‘It’s not rocket science, just cancer genetics.” To the Cancer Biology students who have become my friends- you are all remarkable people. A special acknowledgement goes to my graduating class- Melissa, Rebecca, Ashley, Nick, Tyler and Mengyu. We became a team from day one and I hope we will always have a close bond throughout our careers. Last but not least I acknowledge my family and friends, near and far, for the emotional and moral support. Even though I am far away from home, I have never felt alone. To those lifelong friends who accepted me into your community and hearts during my time in Tampa, I deeply appreciate it. Saba and Sarita- you are like sisters to me. This has been a journey I will never forget. TABLE OF CONTENTS List of Tables ........................................................................................................................... iii List of Figures ........................................................................................................................... iv Abstract ........................................................................................................................... vi Chapter 1- Introduction Introduction to cancer ...................................................................................................... 1 Introduction to chronic lymphocytic leukemia (CLL) ......................................................... 2 Immunobiology of CLL B cells ......................................................................................... 2 Immune dysfunction in CLL ............................................................................................. 4 Therapeutic interventions ................................................................................................ 5 Introduction to epigenetics ............................................................................................... 9 Histone deacetylases .................................................................................................... 10 HDAC inhibitors ............................................................................................................. 11 Chapter 2- Silencing HDAC6 as a therapeutic strategy in chronic lymphocytic leukemia Introduction ................................................................................................................... 14 Background and rationale .............................................................................................. 15 Results Analysis of HDAC6 eXpression in CLL patient samples ..................................... 16 Genetic silencing of HDAC6 in the euTCL1 murine model ................................. 20 RNA sequencing of HDAC6-deficient murine CLL B cells .................................. 24 Antitumor efficacy of ACY738 in murine CLL ..................................................... 27 ACY738 alters proliferative capacity and sensitivity to apoptosis in euTCL1 B cells ............................................................................................ 30 HDAC6 inhibition also alters proliferation and apoptosis in human CLL via downregulation of BCR signaling ..................................... 32 Synergistic activity of ACY738 and ibrutinib in vitro ............................................ 35 Combinatorial efficacy of ACY738 and ibrutinib in murine CLL in vivo .......................................................................................................... 36 Discussion ..................................................................................................................... 37 Materials and methods .................................................................................................. 40 Chapter 3- HDAC6 inhibition relieves CLL T-cell dysfunction and augments antitumor efficacy of anti-PD-1 Introduction ................................................................................................................... 46 Background and rationale .............................................................................................
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