Date of Graduation
12-2024
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Michael Curran, PhD
Committee Member
Stephanie Watowich, PhD
Committee Member
Gregory Lizee, PhD
Committee Member
Matthew Gubin, PhD
Committee Member
Chantale Bernatchez, PhD
Committee Member
Jason Huse, MD, PhD
Committee Member
Jason Schenkel, MD, PhD
Abstract
The past decade has witnessed remarkable advances in the field of cancer immunotherapy. Immune checkpoint blockade (ICB) has emerged as a cornerstone, achieving long-lasting tumor regression in several types of cancer. However, its effectiveness is often limited, particularly in certain tumor types. Immunologically "cold" tumors, such as pancreatic ductal adenocarcinoma (PDAC), remain clinically unresponsive to ICB, presenting a significant challenge in oncology. Amidst these challenges, the stimulation of the STING pathway via small molecule synthetic agonists has surfaced as a promising strategy. Acting as an in-situ vaccine, STING activation has the potential to transform the immune landscape of cold tumors by inducing inflammatory repolarization, particularly of the myeloid stroma, thus enhancing T cell priming and infiltration. However, systemic delivery of these small molecule STING agonists has been limited by their rapid diffusion and clearance, as well as the associated risks of systemic toxicity, confining their application primarily to intratumoural injections. To overcome these obstacles, my thesis introduces the development and characterization of a novel immune-stimulating antibody conjugate. This innovative conjugate to a tumor antigen-specific antibody leverages our potent synthetic STING agonist, IACS-8803, allowing for targeted systemic delivery specifically to tumor sites. In orthotopic models of PDAC, this approach has demonstrated remarkable efficacy, underscoring its potential as a transformative cancer therapeutic strategy. While the capacity of STING agonists to repolarize myeloid cells and enhance effector cell infiltration into tumors is well-recognized, the intricate molecular mechanisms underlying these effects have remained largely unexplored. Through this work, we uncover a hitherto unknown mechanism by which STING-mediated inhibition of the c-Myc oncogene contributes to the immune repolarization and metabolic reprogramming of tumor myeloid stroma. Additionally, we explore how STING signaling modulates myeloid cell metabolism, inducing a hypometabolic state that may be central to the STING-dependent shift from M2-like to M1-like myeloid phenotypes across the tumor microenvironment. This study not only advances our understanding of the novel mechanisms behind STING pathway activation in myeloid cells, but also opens new avenues for the systemic application of tumor or stromally targeted antibodies payload with synthetic STING agonists to surmount the immunosuppressive barriers posed by cold tumors like PDAC.
Keywords
cGAS-STING, Alternate Splicing, STING isoforms, Immunotherapy, Pancreatic Cancer, Tumour Microenvironment, Myeloid Repolarization, Metabolic Rewiring, c-Myc, Immune-Stimulating Antibo