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A Small Molecule Drug Screening Identifies the Antibiotic Colistin Sulfate As an Enhancer of Nk Cell Cytotoxicity

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A Small Molecule Drug Screening Identifies the Antibiotic Colistin Sulfate As an Enhancer of Nk Cell Cytotoxicity A SMALL MOLECULE DRUG SCREENING IDENTIFIES THE ANTIBIOTIC COLISTIN SULFATE AS AN ENHANCER OF NK CELL CYTOTOXICITY Serena Cortés-Kaplan Thesis submitted to the University of Ottawa in partial Fulfillment of the requirements for the MSc degree in Microbiology and Immunology Department of Biochemistry, Microbiology, and Immunology Faculty of Medicine University of Ottawa © Serena Cortés-Kaplan, Ottawa, Canada, 2021 Abstract Cancer immunotherapy is an encompassing term referring to therapeutic strategies that aim to boost the immune system to fight cancer. These strategies include administering immune cells that have been altered to have greater anti-tumor activity or using biologics and small molecules that target immune components to also promote tumor clearance. Natural Killer (NK) cells are cells of the innate immune system that recognize and kill abnormal cells such as cancer cells and play an important role in the anti-tumor response. Because of their crucial role in tumor immunity, NK cells are prime targets for immunotherapies. Repurposing small molecule drugs is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we screened 1,200 approved drugs from the Prestwick Chemical Library to identify drugs that increase NK cell cytotoxicity. We used a high-throughput luciferase-release cytotoxicity assay to measure the killing of the myeloid leukemia cell line, K562 cells expressing nano luciferase (NL) by NK92 cells, a human NK cell line. From the drug candidates identified from the screening assay, the antibiotic colistin sulfate increased cytotoxicity of the NK92 cell line and unstimulated human NK cells towards K562-NL cells. This increase in NK cytotoxicity was short-lived as pre-treating NK92 cells with colistin for 1 hour or 24 hours did not increase cytotoxicity. Also, we show pre- treating K562-NL target cells with colistin does not sensitize them to NK-mediated killing. Further studies are needed to uncover the mechanism of action of colistin, thus contributing to knowledge of fundamental NK cell biology regarding NK cell cytotoxicity which will aid in identifying additional small molecule drugs that enhance NK cell activity. ii Acknowledgements I would like to acknowledge and thank my supervisor Dr. Michele Ardolino for his guidance and support throughout my time in his laboratory and for the great learning opportunities and experiences that were provided. I would like to thank all past and present lab members for their help, support, and feedback throughout my project. I would like to thank members of the Diallo lab for their help throughout this project. I would like to thank my Thesis Advisory Committee members, Dr. Carolina Ilkow and Dr. Jean-Simon Diallo for their time, suggestions, and feedback. Thank you to laboratories of the Cancer Therapeutics Program at the OHRI for sharing advice, equipment, reagents, and protocols. Thank you to the BMI Department at uOttawa for the education provided. I would also like to thank the OHRI and uOttawa flow cytometry facilities. Finally, a huge thank you to my family and friends who have supported me throughout my studies. iii Table of Contents Abstract ........................................................................................................................................................ ii Acknowledgements .................................................................................................................................... iii Table of Contents ....................................................................................................................................... iv List of Abbreviations ................................................................................................................................. vi List of Figures and Tables ........................................................................................................................ vii 1. Introduction ............................................................................................................................................. 1 1.1. Cancer immunotherapy overview ...................................................................................................... 1 1.2. NK cells overview .............................................................................................................................. 2 1.3. NK cell surface markers, receptors, and cytotoxicity ........................................................................ 2 1.4. NK cells, cancer, and NK cell-based immunotherapies ..................................................................... 4 1.5. Drug repurposing and NK cell drug library screenings .................................................................... 5 1.6. Rationale, Objectives and Aims ......................................................................................................... 5 2. Materials & Methods .............................................................................................................................. 7 2.1. Cell culture......................................................................................................................................... 7 2.2. Reagents and drugs ............................................................................................................................ 7 2.3. Generating K562-NL and A375-NL cells ........................................................................................... 8 2.4. Luciferase-release NK92 cytotoxicity assays ..................................................................................... 9 2.5. Flow cytometry-based cytotoxicity assays ....................................................................................... 10 2.6. Screening of the Prestwick Chemical Library and plate configuration ........................................... 10 2.7. Z’ factor, fold-change and normalization analysis .......................................................................... 11 2.8. Dose-response experiments.............................................................................................................. 12 2.9. Colistin pre-treatment experiments .................................................................................................. 12 2.10. Human PBMC isolation ................................................................................................................. 12 2.11. Human NK cell cytotoxicity assays with colistin treatment ........................................................... 13 2.12. Statistical analysis ......................................................................................................................... 13 3. Results .................................................................................................................................................... 14 3.1. Preparing for a high-throughput drug screening ....................................................................... 14 3.1.1. Establishing K562-NL target cells ................................................................................................ 14 3.1.2. Optimizing conditions for a high-throughput luciferase-release cytotoxicity assay ..................... 15 3.2. Screening the Prestwick Chemical Library ................................................................................. 20 3.2.1. Overview of the Prestwick Chemical Library drug screening ...................................................... 20 iv 3.2.2. Identification of candidate drugs and overall quality of the screening assay .............................. 23 3.3. Validating candidate drugs identified from the Prestwick Chemical Library screening ........ 26 3.3.1. Repeating the drug screening’s experimental conditions with candidate drugs .......................... 26 3.3.2. Determining the optimal concentration and E:T ratio for candidate drugs’ activity ................... 26 3.3.3. Treating NK92 cells seeded at a low E:T ratio with colistin ........................................................ 33 3.3.4. Testing if colistin increases NK92 cell cytotoxicity towards other target cell lines ..................... 33 3.3.5. Pre-treatment of NK92 cells for 24-hours with colistin ................................................................ 38 3.3.6. Pre-treatment of NK92 and K562-NL cells for 1-hour with colistin............................................. 38 3.3.7. Treating primary human NK cells with colistin ............................................................................ 46 4. Discussion............................................................................................................................................... 49 5. Conclusion ............................................................................................................................................. 56 6. References .............................................................................................................................................. 57 7. Contribution from collaborators ......................................................................................................... 68 8. Appendix ................................................................................................................................................ 69 Supplemental Figures ........................................................................................................................... 69 Supplemental
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