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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5054-5063.
Prepublished online as a Blood First Edition Paper on March 18, 2008; DOI 10.1182/blood-2007-12-130609.
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Submitted December 27, 2007
Accepted March 9, 2008
Epigenetic control of MHC-II expression in tumor-associated macrophages by decoy receptor 3
Yung-Chi Chang, Tse-Ching Chen, Chun-Ting Lee, Chih-Ya Yang, Hsei-Wei Wang, Chao-Ching Wang, and Shie-Liang Hsieh*
Department and Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou, Taiwan
Genomics Research Center, Academia Sinica, Taipei, Taiwan
* Corresponding author; email: slhsieh{at}ym.edu.tw.
Decoy receptor 3 (DcR3) is a member of the TNF receptor superfamily and is up-regulated in tumors that originate 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 over-expressing 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.
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