Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3

Abstract

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.

Decoy Receptor 3 Enhances Tumor Progression via Induction of Tumor-Associated Macrophages

“…We previously found that DcR3 modulates macrophage differentiation and activation, as well as suppresses MHC-II expression in TAMs via epigenetic regulation in vitro (33,34). The current study investigated whether DcR3 promotes tumor growth via the modulation of TAMs in vivo.…”

“…DcR3-treated macrophages display attenuated phagocytic activity, with downregulated CD14 and CD16, as well as impaired production of proinflammatory cytokines in response to LPS (33). Recently, we further demonstrated that DcR3 downregulates MHC-II expression in macrophages via epigenetic control, and histone deacetylase (HDAC) inhibitor restores MHC-II expression by reversing DcR3-mediated deacetylation of the promoter of transcription factor CIITA (34). However, whether DcR3 promotes tumor growth and progression via the induction of TAMs in vivo remains to be elucidated.…”

Decoy Receptor 3 Expression in AsPC-1 Human Pancreatic Adenocarcinoma Cells via the Phosphatidylinositol 3-Kinase-, Akt-, and NF-κB-Dependent Pathway

“…Elevated serum concentrations of DcR3 have been detected in patients with various malignant cancers, e.g., cancers of the esophagus, stomach, glioma, lung, colon, rectum, and pancreas (1,4,16,18,19). In tumorigenesis, DcR3 not only helps tumor cells to escape immune surveillance by neutralizing FasL-or lymphotoxin-like, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocyte-mediated cell death (1,2), down-regulating MHC-II expression by tumor-associated macrophages (20), and inducing immune suppression, as described above, but also contributes to the development of a microenvironment suitable for tumor growth, e.g., by inducing angiogenesis (21). DcR3 is therefore a critical factor in tumor progression.…”

Decoy receptor 3 regulates the expression of various genes in rheumatoid arthritis synovial fibroblasts

“…Using microarray, Chang et al revealed that genes characteristically expressed by tumor-associated macrophages were upregulated by DcR3 (30). In the current study, we first demonstrated the expression profiles of genes in RA-FLS regulated by DcR3.…”