Semester

Spring

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Scott Weed

Committee Member

Timothy Eubank

Committee Member

Lori Hazlehurst

Committee Member

Edwin Wan

Committee Member

Herbert Zeh

Abstract

Pancreatic adenocarcinoma (PDAC) is a very aggressive disease with an overall survival rate at 12%. This poor outcome at diagnosis is in part due to the lack of effective treatment options. The aggressive disease and unique tumor microenvironment generated during disease initiation and progression has contributed to the lack of effective therapeutic options. Chemotherapy options have not improved overall survival substantially, the effectiveness of radiation therapy remains controversial, and immunotherapies provide little to no benefit when added to current standards of care. Thus, there is a critical need for new therapeutics that can either target PDAC alone or be added to current standards of care to improve their effectiveness. Neutrophil extracellular traps (NETs) have recently become a potential therapeutic target in PDAC. NETs are a process of neutrophils were they decondense their chromatin and extrude it out into the extracellular space in a net like structure. NETs were originally defined as another anti-microbial function of neutrophils and since then have been implicated in several diseases including pancreatic cancer. NETs are elevated in both human and murine models of PDAC and associated with poor patient outcomes, metastasis, fibrosis, proliferation, immune evasion, and hypercoagulability. Our central hypothesis is that neutrophil extracellular traps are responsible for the formation and maintenance of the immunosuppressive microenvironment, and influence pancreatic stellate cell regulation of angiogenesis, limiting the success of standard of care in PDAC. This body of work sets out to establish the role of NETs in modulating the PDAC TME as well as how surgical treatment of PDAC influences the NET response. We found that NETs influence the immune and blood vessel compartments of the PDAC TME. We also found that surgical removal of the primary tumor induces a NET response in the post-operative period. Lastly, we identified a novel mechanism of NET inhibition with chloroquine inhibiting PAD4 activity. In conclusion, we have identified several influences NETs have on the PDAC TME formation, a NET response due to treatment of PDAC, and a novel mechanism of a current drug used to inhibit NETs. This work provides evidence for combining NET inhibition with current therapies for PDAC in clinical trials to improve efficacy and overall prognosis of patients with PDAC.

Embargo Reason

Publication Pending

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