Other Inflammatory Cells Contribute to Macrophage Polarization
Although TAMs make up the majority of infiltrating leukocytes, they are an integral part of a complex immune network and thus interact with other inflammatory cells. TAMs interact with myeloid-derived suppressor cells (MDSCs) and T cells in the tumor microenvironment, the end result of which is to promote a Th2-type polarized environment with high levels of CD4+ T cells, and low levels of CD8+ cytotoxic T cells, which promotes tumor growth (Figure 1).[43,63]
Certain breast cancers produce CSF-1, CCL2, STAT3 and STAT6, which promote macrophage infiltration and M2 differentiation. High Th2 CD4+ T cells with low CD8+ T cells results in a protumoral environment with increased metastatic risk. Interactions between M2 macrophages and MDSCs lead to high levels of IL-10 and low levels of IL-12, further reinforcing the M2 phenotype and increasing levels of Th2-type CD4+ T cells. These CD4+ T cells produce IL-4, which also polarizes macrophages toward M2, creating a feedback loop. Meanwhile, CD8+ T cells are suppressed, resulting in an overall immune-permissive environment for tumor growth and spread. CSF: Colony-stimulating factor; MDSC: Myeloid-derived suppressor cell.
Contact between TAMs and MDSCs leads to relatively high IL-10 levels and low IL-12 levels, polarizing TAMs toward the M2 phenotype, and increasing levels of type 2 CD4+ T cells. Malignant cells frequently express activated STAT3, resulting in the transcription of cytokines and growth factors that induce STAT3 activation in surrounding stromal cells, causing an amplification loop. STAT3 and STAT6 in the tumor microenvironment also directly polarize macrophages toward the M2 phenotype and increase levels of CD4+ T cells.
These type 2 CD4+ T cells, in turn, increase M2 polarization through the production of IL-4, as demonstrated by Coussens et al. in mouse models, showing that those lacking CD4+ T cells had TAMs that produced type 1 cytokines, while those with CD4+ T cells instead had higher levels of type 2 cytokines and arginase, consistent with an M2 phenotype. Depleting those CD4+ T cells or blocking the activity of IL-4 in these models decreases pulmonary metastases.
M2-polarized macrophages also increase the numbers of MDSCs, which then inhibit T cells, including cytotoxic CD8+ T-cell responses.[43,63] CD8+ T-cell function is increased if M2 macrophages are blocked. One method of doing this is targeting legumain, a molecule overexpressed in M2 macrophages. STAT6 may be another target in modulating the effects of TAMs on cytotoxic T cells, as recent work shows that alternatively activated macrophages also suppress T-cell proliferation in the face of certain infections, a process mediated by STAT6.
Biswas et al. have reported that B cells also have the capacity to polarize macrophages. The recruitment of inflammatory cells to a mouse model of skin cancer has been shown to depend on the presence of B cells, which have been found to produce IL-10 and drive macrophages toward the M2 phenotype.
Additionally, the pattern of lymphocyte distribution may also affect their role in response to tumors, with studies suggesting that tumor-infiltrating lymphocytes have different prognostic significance than lymphocytes scattered in the stroma. All these findings suggest that macrophages act in concert with other inflammatory cells, with TAMs contributing to an overall protumoral environment.
Expert Rev Mol Diagn. 2011;11(1):91-100. © 2011 Expert Reviews Ltd.
Cite this: Tumor-associated Macrophages in Breast Cancer as Potential Biomarkers for New Treatments and Diagnostics - Medscape - Jan 01, 2011.