Author ORCID Identifier

https://orcid.org/0000-0002-9000-9062

Semester

Fall

Date of Graduation

2025

Document Type

Dissertation (Campus Access)

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Tracy W. Liu

Committee Member

Brian B. Boone

Committee Member

Cory Robinson

Committee Member

Timothy Eubank

Committee Member

Eric E. Kelley

Abstract

Approximately half a million people die worldwide because of pancreatic ductal adenocarcinoma (PDAC). It is currently the third leading cause of cancer death in the United States, with a five-year survival rate of less than 13%. Treatments like immunotherapy and chemotherapy are ineffective in PDAC due to immunosuppressive tumor microenvironment, in which myeloid cells are a major component. One key mechanism through which myeloid cells promotes immunosuppression involves increased production of reactive oxygen species. Myeloperoxidase (MPO), a heme-containing enzyme abundantly expressed in activated neutrophils, is a major source of reactive oxygen species. While MPO is critical for antimicrobial defense, emerging evidence implicates its involvement in tumor progression and immune evasion. This dissertation investigates the contribution of MPO to PDAC progression and therapeutic resistance using both subcutaneous and orthotopic murine models, complemented by analysis of human PDAC samples. Elevated MPO expression and activity were observed in human and mouse PDAC samples, identifying MPO as a potential therapeutic target. Genetic deletion or pharmacologic inhibition of MPO enhanced the efficacy of immunotherapy in the subcutaneous PDAC model. To enable real-time in vivo tumor monitoring, PDAC cells were engineered to express click beetle green luciferase, and a strategy was developed to evaluate the immunogenicity of reporter constructs— overcoming immune rejection issues associated with red firefly luciferase tumor labeling. In an orthotopic PDAC model, MPO inhibition delayed tumor growth, reduced stromal collagen level, and improved chemotherapy response. Consistent with these findings, elevated MPO activity in patient samples was associated with poor chemotherapy response. MPO deficiency in neutrophils reduced reactive oxygen species levels, immunosuppressive cytokine secretion, and impaired neutrophil extracellular trap formation, resulting in increased infiltration and activation of cytotoxic T and natural killer cells within the tumor microenvironment. Given the link between MPO-derived reactive oxygen species and neutrophil extracellular trap formation, a complementary focus of this work was to develop a non-invasive imaging strategy to monitor neutrophil-mediated inflammation and neutrophil extracellular trap formation using the bioluminescence probe L-012. L-012 signal intensity positively correlated with neutrophil extracellular trap formation in both murine and patient-derived neutrophils, suggesting its potential use as a surrogate marker of NETosis.

Collectively, this dissertation establishes MPO as a relevant therapeutic target in PDAC by demonstrating its involvement in modulating tumor growth, shaping the immune microenvironment, and influencing treatment response. These findings provide preclinical evidence supporting the therapeutic potential of combining MPO inhibition with standard PDAC treatments to enhance efficacy and improve patient outcomes.

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