Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β–activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.

中文翻译：

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NF- κ乙肿瘤的早期发育过程中调节GDF-15来抑制巨噬细胞的监视

巨噬细胞被发展中的肿瘤所吸引，可以参与免疫监视以消除赘生性细胞。作为响应，肿瘤细胞利用NF-κB抑制这种杀伤活性，但其自我保护的机制尚不清楚。在这里，我们报告肿瘤细胞和巨噬细胞之间的这种动态相互作用是由被确定为生长和分化因子15（GDF-15）的可溶性因子整合在一起的。在体外，巨噬细胞中的肿瘤来源的GDF-15信号可通过抑制TNF和一氧化氮（NO）的产生来抑制其促凋亡活性。在体内，Ras中的GDF-15耗竭驱动的肿瘤异种移植和胰腺癌的原位模型延迟了肿瘤的发展。该延迟与浸润的抗肿瘤巨噬细胞增加有关。此外，GDF-15的产生直接受NF-κB调节，而活化的NF-κB和GDF-15在人胰腺癌的上皮管中的共定位也支持该观察。从机理上讲，我们发现GDF-15通过抑制TGF-β活化激酶（TAK1）传递给NF-κB的信号来抑制巨噬细胞的活性，从而阻止TNF和NO的合成。根据这些结果，我们认为NF-κB/ GDF-15调控轴对于肿瘤细胞在肿瘤发生早期避开巨噬细胞免疫监视具有重要意义。