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: 9.28). 07/2010; 70(14):5728-39. DOI: 10.1158/0008-5472.CAN-09-4672
Source: PubMed

ABSTRACT 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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Available from: Jo Van Ginderachter, Dec 26, 2013
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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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    • "Although some studies have reported that high macrophage infiltration is associated with improved survival ( Lackner et al , 2004 ; Forssell et al , 2007 ; Zhou et al , 2010 ; Algars et al , 2012 ; Edin et al , 2012 ; Kinouchi et al , 2012 ) , recent work that has identified the two main subpopulations of macrophages present in the tumour microenvironment suggests a more complex relationship between macrophage infiltration and survival ( Sica et al , 2006 ; Solinas et al , 2009 ) . Indeed , it has been reported that the distribution of the M1 and M2 subpopulations of macrophages in the tumour microenvironment may influence survival and that these subpopulations may localise to different areas of the tumour depending on the prevailing conditions , including tissue hypoxia ( Movahedi et al , 2010 ; Laoui et al , 2011 ; Richards et al , 2012d ) . Indeed , it has long been recognised that TAMs localise to hypoxic regions of the tumour microenvironment ( Harris , 2002 ) . "
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    • "Such complexity likely indicates diverse TAM programming in different microenvironments within individual tumors (Lewis and Pollard, 2006; Qian and Pollard, 2010; Ruffell et al., 2012a; Squadrito and De Palma, 2011). For example, M2-like TAMs reside in both perivascular and hypoxic regions of different mouse and human tumors (Mazzieri et al., 2011; Movahedi et al., 2010; Pucci et al., 2009). A population of vessel-associated TAMs—also referred to as TIE2-expressing monocytes/macrophages (TEMs)—is required for tumor angiogenesis (De Palma et al., 2005) and displays a profoundly M2-skewed phenotype characterized by enhanced expression of scavenger receptors (e.g., MRC1 and CD163) and relatively low levels of MHCII molecules and proinflammatory cytokines (Pucci et al., 2009; Squadrito et al., 2012). "
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