TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth.
TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth.
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DOI：
10.1038/onc.2010.619
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发表时间：
2011-05-26
期刊：
影响因子：
8
通讯作者：
Keshamouni, V. G.
中科院分区：
文献类型：
--
作者：
Standiford, T. J.;Kuick, R.;Bhan, U.;Chen, J.;Newstead, M.;Keshamouni, V. G.
肿瘤相关巨噬细胞（Tumor associated macrophages, tam）是肿瘤微环境（Tumor microenvironment， TME）中观察到的免疫细胞浸润的主要组成部分。存在于TME中的因子包括TGF-β，允许肿瘤绕过宿主介导的免疫反应，促进肿瘤进展。然而，涉及的分子机制尚不清楚。toll样受体（TLRs）是免疫细胞先天免疫反应的重要介质，其激活可触发抗肿瘤反应所需分子的产生。白细胞介素受体相关激酶(IRAK)-M是一种非活性丝氨酸/苏氨酸激酶，主要在巨噬细胞中表达，是TLR信号的有效负调节因子。本研究表明，在同基因肺癌小鼠模型中，tam表达的IRAK-M水平明显高于腹腔巨噬细胞（PEMs）。与野生型动物相比，在IRAK-M−/−小鼠中皮下植入LLC细胞导致肿瘤生长减少5倍。此外，与WT型tam相比，从IRAK-M - / -小鼠中分离的tam表现出经典活化（M1）而非选择性活化（M2）表型的特征，这可以通过IL-12、IFN-γ和iNOS的更高表达来证明。人肺癌细胞在人PBMCs共培养时诱导IRAK-M表达。肿瘤细胞诱导的IRAK-M的表达依赖于TGF-β通路的激活。同样，用TGF-β处理人pbmc或小鼠巨噬细胞系RAW 264.4，可诱导IRAK-M表达。有趣的是，在439例人肺腺癌肿瘤中，IRAK-M基因表达与肺癌患者的低生存率相关。总之，我们的数据表明，TGF-β依赖性诱导IRAK-M表达是肿瘤规避巨噬细胞抗肿瘤反应的重要临床相关机制。
Tumor associated macrophages (TAMs) constitute a major component of the immune cell infiltrate observed in the tumor microenvironment (TME). Factors present in the TME including TGF-β, allow tumors to circumvent host mediated immune responses to promote tumor progression. However, the molecular mechanism(s) involved are not clear. Toll-like receptors (TLRs) are important mediators of innate immune responses by immune cells, whose activation triggers the production of molecules required for anti-tumoral responses. Interleukin receptor associated kinase (IRAK)-M is an inactive serine/threonine kinase, predominantly expressed in macrophages and is a potent negative regulator of TLR signaling. Here we show that TAMs express significantly higher levels of IRAK-M compared to peritoneal macrophages (PEMs) in a syngeneic mouse model of lung cancer. Subcutaneous implantation of LLC cells in IRAK-M−/− mice resulted in a five-fold reduction in tumor growth, as compared to tumors in wild type animals. Furthermore, compared to WT TAMs, TAMs isolated from IRAK-M−/− mice displayed features of a classically activated (M1) rather than alternatively activated (M2) phenotype, as manifest by greater expression of IL-12, IFN-γ, and iNOS. Human lung cancer cells induced IRAK-M expression in human PBMCs when co-cultured together. Tumor cell-induced expression of IRAK-M was dependent on the activation of TGF-β pathway. Similarly, treatment of human PBMCs or mouse macrophage cell line, RAW 264.4, with TGF-β, induced IRAK-M expression. Interestingly, IRAK-M gene expression in 439 human lung adenocarcinoma tumors correlated with poor survival in patients with lung cancer. Together, our data demonstrates that TGF-β-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages.
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