Plectin as an Architect of Immune Evasion in Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma is the 3rd leading cause of cancer-related deaths in the United States, and the incidence is steadily increasing. Its lethality stems from multiple factors, including late-stage diagnosis due to lack of clinical presentation, unreliable diagnostic markers and methods, and the influence of both cell-intrinsic and cell-extrinsic mechanisms that drive disease progression, metastasis, and therapeutic resistance. However, a biomarker and therapeutic target discovered nearly two decades ago holds immense therapeutic promise – plectin. Kelly et al. pioneered a phage display-based proteomic approach that identified plectin as an abundant target exclusively expressed on the cell surface of malignant tissue, termed cancer-specific plectin (CSP). Since then, many CSP-targeting moieties have been leveraged to enhance tumor-specific accumulation of imaging agents and drug delivery systems, most of which have been studied in PDAC. Plectin has since been shown to aggravate malignant hallmarks, including sustained proliferative capacity, enhanced migration and invasion, and evading cell death, and therapeutic targeting of CSP has been shown to mitigate these hallmarks. Results from a first-of-its-kind Phase I/II clinical trial demonstrated that therapeutic targeting of CSP is safe and can stabilize disease progression in patients with treatment refractory sold tumors, including those with pancreatic cancer. Thus, the overarching goal of this dissertation was to expand our knowledge of plectin’s functional repertoire and evaluate CSP-targeted therapy for patient stratification and the rational choice for combination therapies.
Chapter 1 provides an overview of the cell-intrinsic and cell-extrinsic factors that contribute to the initiation and progression of PDAC, and how these factors contribute to a notoriously therapeutic-resistant neoplasm. Then, we will detail how plectin was identified as a novel biomarker and compare plectin function in maintaining homeostasis and contributing to malignancy. The end of this chapter will highlight plectin’s clinical utility and the opportunities its cell-surface localization presents. In Chapter 2, we describe the ground-breaking discovery of plectin as a novel immunomodulator in PDAC, and how therapeutic targeting of CSP initiates a robust anti-tumoral immune response dependent on CD8+ T cell cytotoxicity. Chapter 3 describes ongoing efforts investigating the relationship between plectin and tumor-associated macrophages. Finally, in Chapter 4, we present future directions, summarize the main conclusions from our studies, and highlight the significance of plectin’s immunomodulatory functions and the future of diagnostics and therapeutics in combating PDAC.
Collectively, this dissertation highlights the discovery of a protein not previously linked to immune regulation in PDAC, unveiling an uncharted mechanism of immune modulation within the tumor microenvironment, uncovering new therapeutic opportunities, and advancing our understanding of the complex interplay between PDAC and the immune system.