title: Decoy receptor 3 enhances tumor progression via induction of tumor-associated macrophages.
abstract: Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues. Decoy receptor 3 (DcR3), a member of the TNFR superfamily, is overexpressed in tumor cells and is capable of modulating host immunity as either a neutralizing decoy receptor or an effector molecule. Upregulation of DcR3 has been observed to correlate with a poor prognosis in various cancers. However, the mechanisms underlying the DcR3-mediated tumor-promoting effect remain unclear. We previously demonstrated that DcR3 modulates macrophage activation toward an M2-like phenotype in vitro and that DcR3 downregulates MHC class II expression in TAMs via epigenetic control. To investigate whether DcR3 promotes tumor growth, CT26-DcR3 stable transfectants were established. Compared with the vector control clone, DcR3-transfectants grew faster and resulted in TAM infiltration. We further generated CD68 promoter-driven DcR3 transgenic (Tg) mice to investigate tumor growth in vivo. Compared with wild-type mice, macrophages isolated from DcR3-Tg mice displayed higher levels of IL-10, IL-1ra, Ym1, and arginase activity, whereas the expression of IL-12, TNF-α, IL-6, NO, and MHC class II was downregulated. Significantly enhanced tumor growth and spreading were observed in DcR3-Tg mice, and the enhanced tumor growth was abolished by arginase inhibitor N-ω-hydroxy-l-norarginine and histone deacetylase inhibitor sodium valproate. These results indicated that induction of TAMs is an important mechanism for DcR3-mediated tumor progression. Our findings also suggest that targeting DcR3 might help in the development of novel treatment strategies for tumors with high DcR3 expression.
authors.affiliation: Department of Otolaryngology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Hsin-Chuan
authors.initials: HC
authors.lastname: Chang
authors.forename: Keng-Li
authors.initials: KL
authors.lastname: Lan
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Lee
authors.forename: Chih-Ya
authors.initials: CY
authors.lastname: Yang
authors.forename: Nien-Jung
authors.initials: NJ
authors.lastname: Chen
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Tarng
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008262:Macrophage Activation / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D053323:Receptors, Tumor Necrosis Factor, Member 6b