Notch Signaling Determines the M1 versus M2 Polarization of Macrophages in Antitumor Immune Responses
Notch Signaling Determines the M1 versus M2 Polarization of Macrophages in Antitumor Immune Responses
复制标题
Notch 信号决定抗肿瘤免疫反应中巨噬细胞的 M1 与 M2 极化
DOI：
10.1158/0008-5472.can-10-0269
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发表时间：
2010-06-15
期刊：
影响因子：
11.2
通讯作者：
Han, Hua
中科院分区：
文献类型：
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作者：
Wang, Yao-Chun;He, Fei;Han, Hua
巨噬细胞是重要的肿瘤浸润细胞，在肿瘤生长和转移中起关键作用。巨噬细胞以极化方式参与对肿瘤的免疫反应：经典的M1巨噬细胞产生白细胞介素（IL）12以促进杀肿瘤反应，而M2巨噬细胞产生IL 10并帮助肿瘤进展。巨噬细胞极化的机制尚不清楚。在这里，我们表明，M2样肿瘤相关巨噬细胞（TAM）在小鼠肿瘤模型中具有较低水平的Notch通路激活。Notch信号的强制激活增加了产生IL 12的M1巨噬细胞，无论是否应用M1或M2诱导剂。当Notch信号被阻断时，M1诱导剂诱导M2反应，而M1则被牺牲。经典Notch信号传导中缺乏的巨噬细胞显示TAM表型。巨噬细胞中Notch信号的强制激活增强了它们的抗肿瘤能力。我们进一步表明，RBP-J介导的Notch信号通过SOCS3调节M1对M2极化。因此，Notch信号传导在确定巨噬细胞的M1相对于M2极化中起关键作用，并且受损的Notch途径活化将导致M2样TAM。这些结果为巨噬细胞极化的分子机制提供了新的见解，并通过Notch信号转导调节巨噬细胞极化来阐明癌症的新疗法。Cancer Res; 70（12）; 4840 - 9.（C）2010年AACR。
Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch signaling showed TAM phenotypes. Forced activation of Notch signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J-mediated Notch signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch signaling. Cancer Res; 70(12); 4840-9. (C)2010 AACR.