Graduation Date

Summer 8-6-2021

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Immunology, Pathology & Infectious Disease

First Advisor

Dr. Rakesh K. Singh

Abstract

Pancreatic cancer (PC) remains a challenge to modern-day cancer therapeutics, with a dismal five-year survival rate of 10%. Due to the pancreas's location and desmoplasia surrounding it, patients receive late diagnoses and fail to respond to chemotherapy regimens. Tumor-promoting inflammation, one of the emerging hallmarks of cancer, contributes to tumor cells' survival and proliferation. This inflammation is often the result of infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME).

Neutrophils, one of the most prominent immune cells in our body, play an essential role in sustaining this smoldering inflammation observed in the TME. Previously, our group has shown that these neutrophils are complicit in breast cancer progression and even metastasis. With a similar rationale in mind, this study focuses on how neutrophils invading the TME, also known as tumor-associated neutrophils (TAN's), correlate with disease progression in pancreatic cancer. Our data demonstrated that TAN infiltration is associated with disease progression.

Furthermore, to understand this TAN infiltration, we theorized that the TME plays a significant role in TAN recruitment and TAN proliferation. Our previous work elucidated TAN recruitment by showing increased expression of chemokines in the TME. We also examined TAN and tumor cell interaction in vitro and observed increased tumor cell survival and decreased neutrophil survival. This is theoretically explained by the increased propensity of neutrophils to undergo NETosis and form neutrophil extracellular traps, which have also been shown to correlate with disease progression. Our data suggested neutrophil differentiation in the TME leads to the upregulation of multiple chemokines and, in theory, explains the high TAN infiltration observed in the TME. Together, these data suggest the critical role of TAN and tumor cell interaction in the TME.

Available for download on Wednesday, August 03, 2022

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