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Immune suppression: A link between inflammation and cancer

by Bunt, Stephanie Kirstin, Ph.D., University of Maryland, Baltimore County, 2007, 257 pages;
AAT 3316029

Clinical and experimental evidence supports the concept that chronic

inflammation contributes to cancer development and progression; however, the
mechanisms underlying this relationship are poorly understood. Experimental
observations suggest several inflammatory processes, critical for the
inflammatory response, may promote malignant growth, such as the induction
of DNA damage, the promotion of angiogenesis, and the production of growth
and survival factors. Tumor progression is also accompanied by the
accumulation of myeloid-derived suppressor cells (MDSC), which cause a
global and profound immune suppression. I hypothesized that inflammation may
support malignant growth through the induction and expansion of MDSC,
thereby inhibiting immune surveillance and anti-tumor immunity, and
facilitating malignant cell transformation and proliferation. To study the
association between inflammation and immune suppression in the context of
tumor progression, an inflammatory tumor microenvironment was created and
modulated using: (1) 4T1 mammary carcinoma cells engineered to secrete the
pro-inflammatory cytokine IL-1, (2) 4T1 cells engineered to secrete the proinflammatory cytokine IL-6, (3) IL-1R-deficient mice, which have a reduced
potential for inflammation, (4) and IL-1Ra-deficient mice, which have an
increased potential for inflammation. Chapter 1 introduces the inflammatory
response and the link between inflammation and malignancy, focusing on key
pro-inflammatory mediators and their roles in tumor progression. The results in
Chapter 2 demonstrate that chronic inflammation promotes the induction and
expansion of a more potent suppressive population of MDSC, thereby
enhancing tumor growth and reducing survival. In Chapter 3, the results show
that a reduction in inflammation significantly delays MDSC induction, leading to
a reduction in both primary and metastatic tumor growth. The data in Chapter 4
demonstrate that chronic inflammation promotes and enhances potent type-2
immune responses by MDSC through a mechanism dependent on the Toll-like
receptor 4 pathway. In summary, this thesis introduces a novel pathway
linking inflammation and cancer, demonstrating that tumor progression in the
context of chronic inflammation leads to a more rapid induction and expansion
of MDSC, thereby inhibiting tumor immune surveillance mechanisms, resulting
in enhanced malignant progression.