Intratumoral Sting Activation Sensitizes Poorly Immunogenic Cancers to Checkpoint Blockade Immunotherapy

<p>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 <em>in vitro </em>and <em>in vivo</em> 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 <em>in vitro </em>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2018

Authors dc:creator

• Ager, Casey
• <p>0000-0003-0507-700X</p>

Contributors dc:contributor

• Dr. Michael A. Curran
• Dr. James P. Allison
• Dr. Joya Chandra

• STING
• Macrophage
• MDSC
• Pancreatic Cancer
• Prostate Cancer
• Cancer Immunotherapy
• Checkpoint Blockade
• Medical Immunology
• Medicine and Health Sciences
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/908

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1955