Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes

Department of Molecular and Cellular Interactions, VIB, Cellular and Molecular Immunology and Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Cancer Research (Impact Factor: 9.33). 07/2010; 70(14):5728-39. DOI: 10.1158/0008-5472.CAN-09-4672
Source: PubMed


Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6C(hi)CX(3)CR1(low) monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally "re-educating" the TAM compartment.

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    • "The macrophage mannose receptor (MMR) is a transmembrane glycoprotein that is expressed on macrophages 90, which is primarily responsible for endocytic clearance of certain glycoproteins and phagocytosis of unopsonized microorganisms. It has been reported that certain components of the tumor stroma, especially in the hypoxic areas, that are highly pro-angiogenic overexpress MMR, which plays an important role during tumor growth and related biological processes such as angiogenesis, metastasis, and immune suppression 91. Therefore, MMR is an attractive marker for non-invasive molecular imaging of tumor-associated macrophages. "
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    • "We confirmed that co-cultured macrophages differentiated into TAMs (M2 macrophages), as indicated by the increased expression of the TAM-specific markers Cd163 and Mmp9 (Figure 1A) [23]. Macrophages can differentiate toward M1 (classically activated by LPS) or M2 (TAMs, alternatively activated often by tumor hypoxia or selected interleukins) phenotypes [24]. The present experiments show that culture of macrophages in CSF-1 (control macrophages) maintained their proliferation but did not induce polarization (Figure 1A). "
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    • "). Macrophages were revealed to have had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed (Movahedi et al., 2010). Our results were consistent with this completion in normal mice, while in immunized mice, a significant lower level of macrophages was shown as tumor growth. "
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