title: The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues.
abstract: It has become evident that the tumor microenvironment plays a pivotal role in the maintenance of cancerous growth. One of the acquired functions of the tumor microenvironment is the suppression of immune responses. Indeed, blocking the inhibitory pathways operational in the microenvironment results in enhanced T-cell-dependent, anti-tumor immunity. Chemotherapeutic drugs not only directly kill tumor cells but also shape the tumor microenvironment and potentiate anti-tumor immunity. Here, we demonstrate that the chemotherapeutic compound oxaliplatin acts as a double-edged sword. Besides killing tumor cells, oxaliplatin bolsters immunosuppressive pathways, resulting in decreased activation of T cells by human plasmacytoid dendritic cells (pDCs). Exposure to oxaliplatin markedly increased expression of the T-cell inhibitory molecule programmed death receptor-ligand 1 (PD-L1) on human pDCs and also TLR9-induced IFNα secretion. Furthermore, oxaliplatin decreased TLR-induced STAT1 and STAT3 expression, and NF-κB-mediated responses. The oxaliplatin induced upregulation of PD-L1 and downregulation of costimulatory molecules CD80 and CD86 resulted in decreased T-cell proliferation. Our results demonstrate that platinum-based anticancer drugs adapt TLR-induced signaling in human pDCs and myeloid DCs (mDCs), thereby downgrading their immunostimulatory potential.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Jurjen
authors.initials: J
authors.lastname: Tel
authors.forename: Stanleyson V
authors.initials: SV
authors.lastname: Hato
authors.forename: Ruurd
authors.initials: R
authors.lastname: Torensma
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Buschow
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Lesterhuis
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000276:immunology; D002454:Cell Differentiation; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D050794:STAT1 Transcription Factor / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C508600:IL6 protein, human; D007370:Interferon Type I; D015850:Interleukin-6; D009944:Organoplatinum Compounds; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D000077150:Oxaliplatin