Differential macrophage programming in the tumor microenvironment

Abstract

Of the multiple unique stromal cell types common to solid tumors, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. The protumor properties of TAMs derive from regulation of angiogenic programming, production of soluble mediators that support proliferation, survival and invasion of malignant cells, and direct and indirect suppression of cytotoxic T cell activity. These varied activities are dependent on the polarization state of TAMs that is regulated in part by local concentrations of cytokines and chemokines, as well as varied interactions of TAMs with normal and degraded components of the extracellular matrix. Targeting molecular pathways regulating TAM polarization holds great promise for anticancer therapy.

Figure 1

TAM localization within unique tumor microenvironments. Centrally displayed is an immunofluorescent confocal micrograph of F4/80⁺ macrophages (red) within a late-stage tumor from the MMTV-PyMT mouse model of mammary carcinogenesis. Also shown are areas of hypoxia detected with pimonidazole (yellow), functional vasculature as revealed by perfusion with tomato lectin (green) and DAPI nuclear stain (blue). Clockwise from top left insets display enlarged graphical representations of TAMs within a hypoxic region, at a locally invasive edge, in a normoxic area within the tumor, and associated with the vasculature.

Figure 2

TAMs as central regulators of the tumor microenvironment. Factors that promote the polarization of TAMs towards a pro-tumor phenotype (a–c) can be subdivided into those derived from the immune system, actively produced by tumor cells, or resulting from tissue stress. (a) From leukocytes, this includes cytokines and other soluble factors such as immune complexes. (b) Neoplastic cells can produce chemokines that recruit macrophages, including CSF1 and CCL2 depending on the tissue involved, as well as directly producing immunosuppressive molecules such as IL-10 and PGE₂. (c) Signs of dysregulated tissues include leaky vasculature, hypoxia, ECM remodeling and cell death. These signals all direct the pro-tumor functions of TAMs (d–f) including immune suppression, tumor cell dissemination, and promoting angiogenesis. (d) Immune suppression can occur through soluble or cell surface mediators, and may be indirect such as through the recruitment of regulatory T cells. (e) Neoplastic cell invasion of ectopic tissue can be promoted through directed release of cytokines such as EGF, or through protease-dependent ECM remodeling that may directly affect neoplastic migration or increase chemoattractant bioavailability. (f) In addition to the interplay of TAMs with endothelial cells through production of VEGFA and other angiogenic factors, subsets of TAMs expressing the Tie2 receptor interact with mural cells/pericytes to regulate vascular structure.