Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Robert H. Vonderheide

Abstract

The cytokine milieu in the tumor microenvironment plays a key role in modulating the immune response either in favor of or against tumorigenesis. For many tumors, this complex network of cytokine and immune interactions represent a formidable means of escape from immune surveillance. These cytokine networks are particularly important in pancreatic ductal adenocarcinoma (PDA), where a prominent infiltration of immunosuppressive immune populations could be found. Myeloid-derived suppressor cells (MDSCs) have previously been shown to be potent suppressors of anti-tumor immunity in PDA, but the cytokine networks regulating their recruitment to the tumor microenvironment remain incompletely understood. Here, I found that CXCR2 ligand expression is specifically correlated with enrichment of the granulocytic subset of MDSCs (G-MDSCs) in human PDAs. Using a genetically engineered mouse model of PDA, I showed that CXCR2 is required for G-MDSC trafficking to the tumor microenvironment, but not necessary for their systemic differentiation and expansion. The specific lack of G-MDSCs in the tumor microenvironment led to a T cell-dependent inhibition of tumor growth. Expression of CXCR2 ligands in PDA tumor cells can be potently induced by NF-κB activation. These findings describe a cytokine network in PDA where inflammatory signals in the tumor microenvironment drive the expression of CXCR2 ligands and the recruitment of immunosuppressive G-MDSCs. To discover other potentially important cytokine networks, I developed a novel analysis pipeline to reconstruct and compare cytokine networks from whole tumor gene expression data. Using expression of cytolytic genes as a gauge for anti-tumor immune activity, I found that PDA patients with high cytolytic activity have a slight survival advantage compared to those with lower activity. While macrophages were the most influential in tumors with low cytolytic activity, tumors with high cytolytic activity were characterized by increased activity of NK cells, recruitment of B cells, and increased importance of CD8 T cells, CD4 T helper cells, and B cells, among others. I further highlighted the cytokines that might be associated with these immune populations. Therefore, my analysis identified potentially important components of the cytokine network associated with high and low cytolytic activity. Collectively, the work in this thesis suggests that cytokine networks are crucial for maintaining an immunosuppressive microenvironment in cancer. Furthermore, disrupting key components of these networks can tip the balance in favor of cancer immunosurveillance.

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Available to all on Monday, January 18, 2021

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