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Intratumoral STING Activation Sensitizes Poorly Immunogenic Cancers to Checkpoint Blockade Immunotherapy

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Intratumoral STING Activation Sensitizes Poorly Immunogenic Cancers to Checkpoint Blockade Immunotherapy The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2018 Intratumoral STING Activation Sensitizes Poorly Immunogenic Cancers to Checkpoint Blockade Immunotherapy Casey Ager Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medical Immunology Commons, and the Translational Medical Research Commons Recommended Citation Ager, Casey, "Intratumoral STING Activation Sensitizes Poorly Immunogenic Cancers to Checkpoint Blockade Immunotherapy" (2018). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 908. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/908 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. Approval Page INTRATUMORAL STING ACTIVATION SENSITIZES POORLY IMMUNOGENIC CANCERS TO CHECKPOINT BLOCKADE IMMUNOTHERAPY by Casey Ager, B.S. APPROVED: ______________________________ Michael A. Curran, Ph.D. Advisory Professor ______________________________ James P. Allison, Ph.D. ______________________________ Joya Chandra, Ph.D. ______________________________ Kimberly S. Schluns, Ph.D. ______________________________ Stephanie S. Watowich, Ph.D. APPROVED: ____________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Title Page INTRATUMORAL STING ACTIVATION SENSITIZES POORLY IMMUNOGENIC CANCERS TO CHECKPOINT BLOCKADE IMMUNOTHERAPY A DISSERTATION Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Casey Roy Ager, B.S. Houston, Texas December, 2018 Dedication The work of this dissertation is dedicated to my father, Jeffrey Ager, whose example and memory will forever be a guiding light in my life. iii Acknowledgments The work in this dissertation could not have been completed without the guidance, encouragement, and support of an amazing collection of people whom I am incredibly fortunate to have in my life. First and foremost, the mentorship I have received during my time in the Curran lab has been instrumental in the success of this dissertation. Mike, thank you for your endless hours of hard work and the time you’ve invested in teaching me how to be an independent scientist, and for fostering a lab environment that is motivating, exciting, and always so fun. You’ve been an amazing mentor and role model, and you have provided me with many opportunities that have shaped me and accelerated my career as a scientist. Thank you as well to the rest of the Curran lab; members past and present. From 5am (or earlier!) experiments to great conversation and so much laughter in my little corner, it has been an honor, privilege, and joy to work with all of you. There’s not a better lab around to work in and not a nicer group of people to learn from. I would also like to thank the faculty and staff at the GSBS for creating an environment in which I could grow as a student, scientist, and person. The Deans Mike and Shelley have shown me an incredible level of personal support and encouragement since day one, and I am indebted to them for that. To past and current members of my thesis and candidacy committees, thank you for taking time out of your busy schedules to engage with my work and to guide my path through these projects. Special thanks to Dr. Sastry, who has written more recommendation letters for me than I thought could be humanly possible. To my sweet MB, thank you for being there through the twists and turns, ups and downs, and the long hours associated with this thesis. Your support means the world to me! And finally, thank you to my family. Mom, Bryan, Katie, and now little Addie; you have watched me grow from a young little nerd to an older taller nerd, and through all that life has brought us I would not be where I am or who I am without your love and support. iv Abstract INTRATUMORAL STING ACTIVATION SENSITIZES POORLY IMMUNOGENIC CANCERS TO CHECKPOINT BLOCKADE IMMUNOTHERAPY Casey Ager, B.S. Advisory Professor: Michael A. Curran, Ph.D. Unprecedented durable tumor regression can be achieved in patients with checkpoint blockade immunotherapy, yet these responses are rare and are not observed in all tumor types. Castration resistant prostate cancer (CRPC) and pancreatic adenocarcinoma (PDAC) are two common lethal cancers that remain refractory to checkpoint blockade, requiring development of new therapeutic approaches to promote responsivity in patients with these diseases. Both CRPC and PDAC are characterized by an immunosuppressive tumor milieu rich in cells of the myeloid lineage, which regulate T cell activity in many ways independent of the coinhibitory receptor axis. We investigated whether activation of acute inflammatory signaling through the cytosolic DNA sensing pathway component stimulator of interferon genes (STING) could reprogram tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) to support rather than suppress T cell activity, converting CRPC and PDAC to settings in which checkpoint blockade can be effective. To this end, we established therapeutic synergy between cyclic dinucleotide (CDN) STING agonists and checkpoint modulating agents in the multi-focal TRAMP-C2 murine model of CRPC, and described how the balance between systemic efficacy and local pathology can be balanced by modifying CDN dosing frequency. We characterized a novel STING agonist IACS-8803, which possesses potent stimulatory activity and therapeutic efficacy in vitro and in vivo relative to known natural and synthetic clinical CDN compounds. We described the phenotypic and functional effects of CDNs on suppressive MDSCs and TAMs of murine and human origin in the in vitro setting, and utilized high parameter flow cytometry to validate these changes in the tumor microenvironment upon local CDN injection. Utilizing a novel transplantable model of orthotopic PDAC, we confirm that intra-pancreatic delivery of 8803 can synergize with checkpoint blockade to significantly prolong survival in a highly refractory setting. Together, these studies lay the groundwork for translation of CDNs in combination with checkpoint blockade for patients with CRPC and PDAC. v Table of Contents Approval Page ........................................................................................................................i Title Page .............................................................................................................................. ii Dedication ............................................................................................................................ iii Acknowledgments ................................................................................................................ iv Abstract ................................................................................................................................. v Table of Contents ................................................................................................................. vi List of Illustrations ................................................................................................................ ix List of Tables ........................................................................................................................ xi Chapter 1: Introduction ......................................................................................................... 1 1.1: Tumor Immunogenicity: Beyond “Hot” and “Cold” ...................................................... 2 1.1.1: Defining Characteristics of “Hot” and “Cold” Tumors ........................................... 3 1.1.2: Castration Resistant Prostate Cancer (CRPC); a Quintessential “Cold” Tumor ..14 1.1.3: Pancreatic Ductal Adenocarcinoma (PDAC); a Uniquely “Cold” Tumor ..............19 1.1.4: Summary ............................................................................................................26 1.2: Myeloid Immunosuppression: A Critical Barrier to Antitumor Immunity .....................27 1.2.1: Ontogeny of Myeloid Derived Suppressor Cells and Tumor Associated Macrophages ...............................................................................................................28 1.2.2: Mechanisms of T Cell Immunosuppression by MDSCs and TAMs .....................34 1.2.3: Therapeutic Targeting of MDSCs and TAMs in Cancer ......................................39 vi 1.2.4: Summary ............................................................................................................44 1.3: STING: A Powerful Activator of Innate Immunity in the Tumor Microenvironment .....46 1.3.1: Discovery and Characterization of the cGAS-STING Pathway ...........................47 1.3.2: Role
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