Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3
Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3
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DOI：
10.1182/blood-2007-12-130609
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发表时间：
2008-05-15
期刊：
影响因子：
20.3
通讯作者：
Hsieh, Shie-Liang
中科院分区：
文献类型：
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作者：
Chang, Yung-Chi;Chen, Tse-Ching;Hsieh, Shie-Liang
诱饵受体3（DcR 3）是TNF受体超家族的成员，并且在源自多种谱系的肿瘤中上调。DcR 3能够促进血管生成、诱导树突状细胞凋亡和调节巨噬细胞分化。由于肿瘤相关巨噬细胞（TAM）是大多数恶性肿瘤中主要的浸润性白细胞，我们使用微阵列技术来研究DcR 3是否有助于TAM的发展。在TAM表达的DcR 3调节基因中，编码参与MHC II类（MHC-II）依赖性抗原呈递的蛋白质的基因与MHC-II表达的主调节因子（II类反式激活因子，CIITA）一起显著下调。与CIITA启动子相关的ERK和JNK诱导的组蛋白脱乙酰化负责DcR 3介导的MHC-II表达下调。此外，癌细胞中DcR 3的表达水平与TAM上的HLA-DR水平以及胰腺癌患者的总生存时间呈负相关。使用过表达DcR 3的转基因小鼠进一步证实了DcR 3在TAM发育中的作用。这阐明了受损的MHC-II-介导的抗原呈递的TAM的分子机制，并提出了通过抑制DcR 3表达来颠覆TAM诱导的免疫抑制可能代表新疗法设计的靶点的可能性。
Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and is up-regulated in tumors originating from a diversity of lineages. DcR3 is capable of promoting angiogenesis, inducing dendritic cell apoptosis, and modulating macrophage differentiation. Since tumor-associated macrophages (TAMs) are the major infiltrating leukocytes in most malignant tumors, we used microarray technology to investigate whether DcR3 contributes to the development of TAMs. Among the DcR3-modulated genes expressed by TAMs, those that encode proteins involved in MHC class II (MHC-II)dependent antigen presentation were down-regulated substantially, together with the master regulator of MHC-II expression (the class II transactivator, CIITA). The ERK- and JNK-induced deacetylation of histones associated with the CIITA promoters was responsible for DcR3-mediated down-regulation of MHC-II expression. Furthermore, the expression level of DcR3 in cancer cells correlated inversely with HLA-DR levels on TAMs and with the overall survival time of pancreatic cancer patients. The role of DcR3 in the development of TAMs was further confirmed using transgenic mice overexpressing DcR3. This elucidates the molecular mechanism of impaired MHC-II-mediated antigen presentation by TAMs, and raises the possibility that subversion of TAM-induced immunosuppression via inhibition of DcR3 expression might represent a target for the design of new therapeutics.