title: Tumor-educated tolerogenic dendritic cells induce CD3epsilon down-regulation and apoptosis of T cells through oxygen-dependent pathways.
abstract: Defects in the CD3/TCR complex and impairment of T cell function are necessary for tumor evasion, but the underlying mechanisms are incompletely understood. We found that culture supernatants from several types of solid tumor cell lines drove human monocytes to become tolerogenic semimature dendritic cells (TDCs). Upon encountering T cells, the TDCs triggered rapid down-regulation of CD3epsilon and TCR-alpha/beta and subsequent apoptosis in autologous T cells. Consistent with these results, accumulation of immunosuppressive DCs coincided with CD3epsilon down-regulation and T cell deletion in cancer nests of human tumors. The impaired T cell function was mediated by factor(s) released by live TDCs after direct interaction with lymphocytes. Also, the TDC-induced effect on T cells was markedly reduced by blocking of NADPH oxidase but not by inhibition of arginase, inducible NO synthase (iNOS), IDO, or IFN-gamma. Moreover, we found that hyaluronan fragments constituted a common factor produced by a variety of human tumor cell lines to induce formation of TDCs. These observations indicate that tumor microenvironments, including hyaluronan fragments derived from cancer cells, educate DCs to adopt a semimature phenotype, which in turn aids tumor immune escape by causing defects in the CD3/TCR complex and deletion of T cells.
authors: State Key Laboratory of Biocontrol, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors: Dong-Ming
authors: DM
authors: Kuang
authors: Qiyi
authors: Q
authors: Zhao
authors: Jing
authors: J
authors: Xu
authors: Jing-Ping
authors: JP
authors: Yun
authors: Changyou
authors: C
authors: Wu
authors: Limin
authors: L
authors: Zheng
mesh_terms: D017209:Apoptosis; D017252:CD3 Complex / Q000235:genetics*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D006820:Hyaluronic Acid; D007108:Immune Tolerance; D019255:NADPH Oxidases / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology*; D010100:Oxygen / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology*; D019139:Tumor Escape
chemical_list: D017252:CD3 Complex; C115335:CD3E protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta; D006820:Hyaluronic Acid; D019255:NADPH Oxidases; D010100:Oxygen