title: Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2- and Tr1-biased T-cell immunity.
abstract: Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-κB signaling pathways without altering the levels of TNF-α and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10-/- mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3+CD4+LAG-3+CD49b+CD25-Foxp3- Tr1 cells, that was significantly increased without altering the Foxp3+ regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system.
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Woo Sik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kee Woong
authors.initials: KW
authors.lastname: Kwon
authors.affiliation: Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, South Korea.|Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
authors.affiliation: Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Bo Ryeong
authors.initials: BR
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007111:Immunity, Cellular / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C556062:IL10 protein, mouse; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051193:Toll-Like Receptors; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin
keywords: IL-10; Immune response; Immunity; Immunology and Microbiology Section; Tr1 polarization; cisplatin; tolerogenic dendritic cells; toll-like receptor