Date of Award

Spring 5-15-2017

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The immune system plays an essential role in protecting the host organisms against both foreign invaders and self-attacks arisen within the host, such as tumors. Instead of promoting the long-term fitness of the organism, the immune system is often suppressed or hijacked by tumor cells to accelerate the progression of malignancies. Among the key drivers of immune suppression, macrophages are one of the most abundant immune cells present in tumor tissues. High levels of macrophage infiltration in the malignant tissues correlate with negative patient outcome in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies in human beings. Therefore, attempts have been directed towards targeting tumor-associated macrophages (TAMs) to improve the efficacy of cancer treatment. We attempted to target TAM responses in murine PDAC models through inhibiting the colony stimulating factor-1 receptor (CSF1R) signaling pathway. CSF1R signal blockade not only depleted half of the TAMs within the tumor microenvironment, but also functionally reprogrammed the remaining TAM compartment to support anti-tumor T cell responses. More importantly, CSF1R signal blockade sensitized the tumors to T cell checkpoint-based immunotherapies, which failed to achieve clinical efficacy as monotherapies. These findings revealed the potential benefits of targeting TAMs to improve treatment of PDAC patients. However, TAM-targeting strategies have limitations. Optimal TAM-based therapeutic intervention requires in-depth understanding of the sources that supply macrophages to malignant tissues. Towards that end, we investigated the ontogeny of TAMs in murine PDAC models, and identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originate during embryonic development at the yolk sac stage. These cells undergo significant local expansion through in situ proliferation during tumor progression. While monocyte-derived TAMs play more potent roles in tumor antigen presentation, embryonically derived TAMs exhibit profibrotic transcriptional profiles and ex vivo fibrotic activities, indicative of their role in producing and remodeling extracellular matrix molecules. Collectively, these findings uncovered the heterogeneity of TAM origin and functions, and could provide insights into therapeutically targeting different TAM subsets based on the different pathological features of the PDAC microenvironment.

Language

English (en)

Chair and Committee

David G. DeNardo

Committee Members

Daniel C. Link, Gwendalyn J. Randolph, Jason C. Mills, Sheila A. Stewart,

Comments

Permanent URL: https://doi.org/10.7936/K79C6VVN

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