Immune Suppression and Inflammation in the Progression of Breast Cancer
Annual summary rept. 25 Feb 2005-24 Feb 2008
MARYLAND UNIV BALTIMORE
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Epidemiological and experimental evidence supports the concept that chronic inflammation promotes and enhances cancerous growth through several key mechanisms, although these processes are not well understood. Several important mechanisms by which inflammation may initiate and support malignant progression have been previously described, such as the induction of DNA damage, the promotion of angiogenesis and new vasculature, and the production of growth and survival factors. The purpose of this study is to identify a novel mechanism by which chronic inflammation may support and advance tumor progression, through the induction and expansion of immune suppressive mechanisms. We demonstrate that chronic inflammation induces tumor-associated immune-suppression, by enhancing the accumulation of a population of immature myeloid-derived suppressor cells MDSC, which down regulate and inhibit anti-tumor immunity, allowing for the proliferation and outgrowth of transformed cells. To study the association between inflammation and immune suppression in the context of tumor progression, the 4T1 mammary carcinoma cell line engineered to secrete the pro-inflammatory cytokine interleukin 1 beta 4T1IL-1beta was used to create an inflammatory tumor microenvironment. Additionally, IL-1 receptor IL-1R-deficient mice, which have a reduced potential for inflammation, and IL-1 receptor antagonist IL-1Ralpha-deficient mice, which have an increased potential for inflammation, were used to modulate the inflammatory milieu, and the effects of inflammation on primary and metastatic tumor progression and immune suppression were examined. The presence of IL-1beta in the tumor microenvironment promotes the induction and expansion of a more potent suppressive population of MDSC, thereby enhancing tumor growth and reducing survival.
- Medicine and Medical Research