Immune suppression: A link between inflammation and cancer
by Bunt, Stephanie Kirstin, Ph.D., University of Maryland, Baltimore County, 2007, 257 pages; AAT 3316029 (Summary)
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.