Date of Award

2020

Embargo Period

1-1-2025

Document Type

Thesis - MUSC Only

Degree Name

Master of Science (MS)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Denis Guttridge

Second Advisor

Jessica Thaxton

Third Advisor

Ernest Ramsay Camp

Fourth Advisor

John O’Bryan

Fifth Advisor

Michael Ostrowski

Abstract

Studies indicate that growth and differentiation factor 15 (GDF15) is elevated in pancreatic ductal adenocarcinoma (PDAC). However, the relationship between increasing level and function in PDAC development are only beginning to be revealed. Our lab previously showed that GDF15 promotes the initiation of PDAC by functioning as an immunosuppressive factor of inflammatory, anti-tumor macrophages. We report here that GDF15 is also capable of influencing other immune cells within the tumor-microenvironment (TME), specifically T cells. In vitro, we found that when T cells are incubated with conditioned media (CM) from pancreatic tumor cells containing GDF15, both CD4+ and CD8+ T cells proliferation was inhibited. The opposite effect was observed when T cells were grown in CM lacking GDF15. This GDF15 immune suppressive activity was reversed when GDF15 in the CM was inhibited with a neutralizing antibody. In vivo, the conditional ablation of GDF15 in a GEMM of pancreatic cancer led to a reduction in PDAC initiation, which was associated with increased macrophage infiltration. We have also showed that the absence of GDF15 in this setting led to greater survival. Together, these data lead us to speculate that increasing levels of GDF15 in PDAC is relevant to the initiation of tumorigenesis by functioning to immunosuppress both anti-tumor macrophages and CD8+ T cells.

Rights

All rights reserved. Copyright is held by the author.

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Available for download on Wednesday, January 01, 2025

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