Tumor-associated Macrophages in Breast Cancer as Potential Biomarkers for New Treatments and Diagnostics

Rita A Mukhtar; Onouwem Nseyo; Michael J Campbell; Laura J Esserman

Disclosures

Expert Rev Mol Diagn. 2011;11(1):91-100. 

In This Article

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]

Figure 1.

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.[64] 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.[55] STAT3 and STAT6 in the tumor microenvironment also directly polarize macrophages toward the M2 phenotype and increase levels of CD4+ T cells.[43]

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.[65] Depleting those CD4+ T cells or blocking the activity of IL-4 in these models decreases pulmonary metastases.[65]

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.[66] 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.[67]

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,[3] which have been found to produce IL-10 and drive macrophages toward the M2 phenotype.[68]

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.[69] All these findings suggest that macrophages act in concert with other inflammatory cells, with TAMs contributing to an overall protumoral environment.

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