Macrophages and MDSC are present within most solid tumors, where they are major drivers of immune suppression and inflammation. Although the cellular interactions contributing to some of the protumor factors present in the tumor microenvironment have been identified, the etiology of others remains unknown. These factors, in turn, induce the accumulation and enhance the function of immune-suppressive cells, such as regulatory T cells, plasmacytoid dendritic cells, tumor-associated macrophages, and MDSC. Some of these cells engage in cross-talk with each other, resulting in the release of proinflammatory cytokines (e.g., IL-1, IL-6, IL-17, TNF-α), chemokines (e.g., CCL2, CXCL5, CXCL12), growth factors (e.g., TGF-β, GM-CSF, VEGF), and other effector molecules (e.g., S100A8/A9, high-mobility group box 1). The inflammation is driven by proinflammatory mediators that are secreted by tumor cells, various tumor-infiltrating lymphocytes, tumor-associated fibroblasts, and myeloid cells, such as macrophages, dendritic cells, and MDSC. Solid tumors are a complex and frequently inflamed environment. These results suggest that inflammation within solid tumors is regulated by the ratio of tumor cells to MDSC and macrophages and that interactions of these cells have the potential to alter significantly the inflammatory milieu within the tumor microenvironment. In vivo analysis of solid tumors identified IL-6 and IL-10 as the dominant cytokines and demonstrated that these molecules were produced predominantly by stromal cells. Tumor cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. Tumor cells also increased macrophage IL-6 and NO and decreased macrophage TNF-α. Tumor cells increased MDSC IL-6 and vice versa. In vitro studies demonstrated that MDSC-produced IL-10 decreased macrophage IL-6 and TNF-α and increased NO. We focused on IL-6, IL-10, IL-12, TNF-α, and NO, as these molecules are produced by macrophages, MDSC, and many tumor cells are present in most solid tumors and regulate inflammation. To examine potential interactions between these cells, we studied the impact of MDSC, macrophages, and four murine tumor cell lines on each other, both in vitro and in vivo. It is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity however, interactions between tumor cells and MDSC or macrophages are less well studied.
MDSC and macrophages are present in most solid tumors and are important drivers of immune suppression and inflammation.
0 kommentar(er)
