Abstract PL03-02: Inflammation-driven myeloid-derived suppressor cells: co-opting anti-tumor immunity to promote tumor progression

Abstract

Abstract PL03-02 Inflammation facilitates tumor onset and promotes tumor progression through a variety of mechanisms. One of these mechanisms is by activating myeloid-derived suppressor cells (MDSC), a population of cells that block anti-tumor immunity. MDSC are present in most patients and experimental animals with primary and/or metastatic cancer. They inhibit adaptive anti-tumor immunity by preventing the activation of CD4+ and CD8+ T cells, and by blocking innate immunity by inhibiting natural killer cell cytotoxicity and polarizing immunity towards a tumor-promoting type 2 phenotype. Because of their extreme immune suppressive activity, MDSC will be a significant impediment to active immunotherapy in patients with established malignancies. The accumulation and retention of MDSC are driven by multiple pro-inflammatory factors that arise from chronic inflammation and that are produced by malignant cells and by the tumor microenvironment. Multiple pro-inflammatory mediators, including IL-1β, IL-6, prostaglandin E2 (PGE-2), and the S100A8/A9 proteins, accentuate the accumulation and retention of MDSC in tumor-bearing individuals. IL-1β mediates its effects indirectly, while IL-6, PGE-2, and S100A8/A9 proteins appear to directly interact with MDSC through their respective receptors. In addition to increasing the T cell suppressive activity of MDSC, IL-1β increases the cross-talk between MDSC and macrophages. This cross-talk enhances a type 2 immune response that favors tumor progression by increasing MDSC production of IL-10 and decreasing macrophage production of IL-12. MDSC not only respond to these pro-inflammatory molecules, but they also exacerbate an inflammatory tumor microenvironment by synthesizing and secreting proinflammatory mediators, including the S100A8/A9 proteins. As a result, once induced and activated, MDSC maintain an autocrine feedback loop that sustains their levels in the blood, lymph nodes, and at tumor sites. Multiple approaches are being developed to block the induction/activation of MDSC. Since both IL-1β and S100A8/A9 activate MDSC through the NF-κB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients. (Supported by NIH R01CA84232, RO1CA115880) Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL03-02.