ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Immunology, Pathology & Infectious Disease
First Advisor
Rakesh K Singh
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a five-year survival rate of only 13%. Tumor-promoting inflammation and immune evasion are hallmarks that contribute to tumor survival, proliferation, and metastasis and are driven by infiltrating leukocytes and the release of pro-inflammatory cytokines into the tumor microenvironment. Among the infiltrating leukocytes, neutrophils play a critical role in inflammation and immunoregulation, exhibiting both pro- and anti-tumorigenic functions depending on the cancer context.
Our studies investigated the multifaceted role of neutrophils in PDAC progression using patient samples, murine models, and in vitro systems. We observed enhanced neutrophil infiltration and neutrophil extracellular trap formation, which correlated with disease stage and tumor site. CXCR2 and its ligands have emerged as key mediators of neutrophil recruitment, and their expression is associated with a poor prognosis in patients. Moreover, neutrophil recruitment and NET formation promoted an immunosuppressive and inflammatory tumor microenvironment that facilitates tumor persistence and progression. In addition, we confirmed, through decreased iNOS and increased arginase expression, that these neutrophils exhibit a pro-tumorigenic phenotype.
To further explore the mechanisms driving neutrophil persistence, we examined how PDAC-derived factors influence neutrophil survival and function. Conditioned media from PDAC cell lines enhanced neutrophil survival by upregulating anti-apoptotic genes (BCL-2 and BCL-xL) and modulating immunoregulatory molecules, particularly in our cellularly aggressive models. Co-culture experiments revealed reciprocal interactions, with neutrophils promoting PDAC cell proliferation. Neutrophils exposed to PDAC factors displayed reduced ROS activity but increased expression of pro-inflammatory cytokines (iNOS, IL-6, TNF-α), further suggesting a phenotypic shift toward a pro-tumorigenic state.
Building on these findings, we identified the neutrophil serine protease (NSP)–serpin axis as a potential mechanism underlying enhanced neutrophil survival in the PDAC TME. Our analysis revealed that neutrophil intrinsic survival is mediated by increased serpin levels accompanied by decreased NSP enzymatic activity, particularly in aggressive PDAC contexts. This imbalance favored neutrophil longevity and contributed to the establishment of a chronic inflammatory and immunosuppressive niche.
Together, our data demonstrate that CXCR2-driven pro-tumorigenic neutrophil recruitment, enhanced NET formation, and dysregulation of the NSP–serpin axis collectively promote neutrophil persistence, immunosuppression, and inflammation in PDAC, ultimately driving disease progression and poor clinical outcomes.
Rights
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Recommended Citation
Sturgeon, Reegan, "Neutrophil–Pancreatic Cancer Interplay Defines a Microenvironmental Axis that Sustains Neutrophil Survival and Pro-tumorigenic Reprogramming" (2026). Theses & Dissertations. 1034.
https://digitalcommons.unmc.edu/etd/1034