Fig. 1

Direct and indirect regulation of immune suppression or stimulation by tumor associated macrophage subtypes. Macrophage polarization within the tumor microenvironment is highly dependent on the local cytokine milieu which originates either from tumor cells, other stromal cells such as immune cells or fibroblasts, as well as macrophages themselves. The M2 TAM phenotype is a consequence of the continuous presence of growth factors such as colony-stimulating factor-1 (CSF1) as well as CD4+ T cell-derived T_h2 cytokines interleukin (IL)-4, IL-13 and IL-10 (5). Besides the direct tumor growth promoting abilities of M2 TAM (not illustrated here), these macrophages efficiently suppress immune effector functions that are able to contribute to tumor cell elimination (3,4). This silencing of immune effector cells is achieved by producing cytokines and enzymes that may directly suppress effector cells or indirectly via other immune cell types such as intratumoral dendritic cells (DC), T regulatory cells (Treg cells) and Type 2 helper T cells. In contrast, M1 TAM are attributed with tumoricidal functions and are generated in the presence of GM-CSF and pro-inflammatory stimuli like IFNγ, LPS or TNFα (5). Tumoricidal function can either be achieved through direct killing of tumor cells or by producing cytokines/chemokines that are activating/recruiting other immune stimulatory immune cells and inhibiting immune suppressive cells like Treg cells. Eventually a predominant M1 TAM phenotype may result in an anti-tumor immune effector cell activation. Published data suggest that tumor promoting and immune suppressive M2 macrophages/TAM are dependent on CSF1R mediated signals (31) making this receptor an attractive target to eliminate or repolarize these cells