Semester
Spring
Date of Graduation
2024
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Committee Chair
Elena Pugacheva
Committee Member
Emidio Pistilli
Committee Member
Scott Weed
Committee Member
Cory Robinson
Committee Member
Brian Boone
Abstract
The 5-year-survival rate for pancreatic ductal adenocarcinoma (PDAC) is only 12% due in part to a lack of therapeutic strategies that target the pathophysiology of the disease. The only known curative therapy is surgical resection of the PDAC tumor, but only 20% of patients are eligible at the time of presentation. To improve outcomes for patients, new therapeutic options are needed. The PDAC tumor microenvironment (TME) is uniquely fibrotic and hypoxic, which is in part driven by the immune cell composition in the TME. Myeloid cells are a prominent immune infiltrate within the PDAC TME, so these cells have been an important research focus when considering therapeutic targets. Despite research into myeloid populations in PDAC, targeting these cells clinically has proven challenging with only modest improvements in outcomes. Thus, better strategies are needed to understand these highly plastic immune cells. Further, a better understanding of how myeloid cells can be influenced by other innate immune cells, particularly neutrophils, is needed since these two cell populations are known to interact in settings outside of cancer. The central hypothesis for this dissertation is that different myeloid cell subpopulations can differentially influence patient outcomes in PDAC. Further, we suggest that neutrophil extracellular traps (NETs), a process through which activated neutrophils released their intracellular contents into the circulation or extracellular space that has been implicated in PDAC pathogenesis, may play a role in regulating these myeloid cell populations. Herein, we utilize single nuclear assay for transpose accessible chromatin sequencing (snATAC-Seq) of frozen PDAC tissues to show that dendritic cell infiltrates improve outcomes in PDAC patients. Further, we explore monocyte recruitment in the presence and absence of NETs to implicate NETs in the regulation of monocyte infiltration into the PDAC TME. The present work provides evidence of an important role for myeloid subpopulations in the PDAC TME and implicates NETs as an important modifier for myeloid cell recruitment.
Recommended Citation
Pratt, Hillary Gabrielle, "Interactions Between Myeloid Cells and Neutrophil Extracellular Traps in Pancreatic Ductal Adenocarcinoma" (2024). Graduate Theses, Dissertations, and Problem Reports. 12476.
https://researchrepository.wvu.edu/etd/12476
Embargo Reason
Publication Pending