Immunotherapies aimed at activating the host's immune system are promising strategies for the treatment of cancer because of their potential for minimal toxicity to healthy cells and immune memory that may protect against metastatic disease. These active immunotherapies predominantly focus on generating tumor-reactive T-lymphocytes, which are principle mediators of anti-tumor immunity. Disappointingly, clinical trials of cancer vaccines or other active T-cell mediated immunotherapies have not yielded significant patient responses. Since most cancer patients are immune suppressed, these failures are most likely due to the inability of cancer patients to immunologically respond to the immunotherapy agents. Although multiple mechanisms contribute to immune suppression in individuals with cancer, myeloid-derived suppressor cells (MDSC) accumulate in virtually all cancer patients and are a major cause of tumor-induced immune suppression due to their inhibition of both adaptive and innate immune responses. Because of their widespread presence and potent immune suppressive effects, identifying the cellular and molecular mechanisms responsible for MDSC accumulation and suppressive activity may facilitate the development of effective immunotherapy strategies. Chronic inflammation frequently precedes tumor onset and many cancer cells produce pro-inflammatory mediators, suggesting that chronic inflammation contributes to tumorigenesis and tumor. It has been previously demonstrated that inflammation via the pro-inflammatory molecules Interleukin-1beta (IL-1beta) and Toll-like receptor 4 (TLR4) increases either the number or the suppressive activity of MDSC, or both. This causative relationship between inflammation and MDSC induction led us to hypothesize that MDSC not only are an obstacle to immunotherapy, but also contribute to the onset and progression of tumors by inhibiting immune surveillance of newly transformed cells and by blocking natural immunity to established tumors.
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