Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes
Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes
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DOI：
10.1158/0008-5472.can-09-4672
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Van Ginderachter, Jo A.
中科院分区：
文献类型：
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作者：
Movahedi, Kiavash;Laoui, Damya;Van Ginderachter, Jo A.
肿瘤相关巨噬细胞()是肿瘤间质的主要成分。然而，重要的概念，如的异质性和单核细胞前体的性质仍然是推测的。在这里，我们第一次展示了小鼠乳腺肿瘤包含功能不同的TAMs亚群，并为它们的鉴定提供了标记。此外，在寻找祖细胞的过程中，我们发现肿瘤-单核细胞池几乎完全由Ly6C(Hi)Cx(3)CR1(Low)单核细胞组成，这些单核细胞不断地播种肿瘤并更新所有非增殖的亚群。有趣的是，基因和蛋白质图谱表明，不同的群体在分子水平上存在差异，可以根据经典的(M1)巨噬细胞激活范式和替代的(M2)巨噬细胞激活范式进行分类。重要的是，更多的M2样TAM在低氧肿瘤区域富含，在体内具有更好的促血管生成活性，并且随着肿瘤的进展数量增加。最后，研究表明，亚群是较差的抗原提呈者，但可以抑制T细胞的激活，尽管使用了不同的抑制机制。综上所述，我们的数据有助于揭开肿瘤浸润性髓系细胞亚群的复杂性，并为针对特定的亚群提供理论基础，从而以最佳方式“重新教育”亚群。癌症资源；70(14)；5728-39。(C)2010年AACR。
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. Cancer Res; 70(14); 5728-39. (C)2010 AACR.