title: Proinflammatory response of human leukemic cells to dsRNA transfection linked to activation of dendritic cells.
abstract: Leukemic cells exert immunosuppressive effects that interfere with dendritic cell (DC) function and hamper effective antileukemic immune responses. Here, we sought to enhance the immunogenicity of leukemic cells by loading them with the double-stranded (ds) RNA Toll-like receptor 3 (TLR3) ligand polyriboinosinic polyribocytidylic acid (poly(I:C)), mimicking viral infection of the tumor cells. Given the responsiveness of DC to TLR ligands, we hypothesized that the uptake of poly(I:C)-loaded leukemic cells by immature DC (iDC) would lead to DC activation. Primary acute myeloid leukemia (AML) cells and AML cell lines markedly responded to poly(I:C) electroporation by apoptosis, upregulation of TLR3 expression, enhanced expression of major histocompatibility complex (MHC) and costimulatory molecules and by production of type I interferons (IFN). Upon phagocytosis of poly(I:C)-electroporated AML cells, DC maturation and activation were induced as judged by an increased expression of MHC and costimulatory molecules, production of proinflammatory cytokines and an increase of T helper 1 (T(H)1)-polarizing capacity. These immune effects were suboptimal when AML cells were passively pulsed with poly(I:C), indicating the superiority of poly(I:C) transfection over pulsing. Our results demonstrate that poly(I:C) electroporation is a promising strategy to increase the immunogenicity of AML cells and to convert iDC into activated mature DC following the phagocytosis of AML cells.
authors.affiliation: Laboratory of Experimental Hematology, Faculty of Medicine, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: E L J M
authors.initials: EL
authors.lastname: Smits
authors.forename: P
authors.initials: P
authors.lastname: Ponsaerts
authors.forename: A L R
authors.initials: AL
authors.lastname: Van de Velde
authors.forename: A
authors.initials: A
authors.lastname: Van Driessche
authors.forename: N
authors.initials: N
authors.lastname: Cools
authors.forename: M
authors.initials: M
authors.lastname: Lenjou
authors.forename: G
authors.initials: G
authors.lastname: Nijs
authors.forename: D R
authors.initials: DR
authors.lastname: Van Bockstaele
authors.forename: Z N
authors.initials: ZN
authors.lastname: Berneman
authors.forename: V F I
authors.initials: VF
authors.lastname: Van Tendeloo
mesh_terms: D000208:Acute Disease; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D018274:Electroporation; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D011070:Poly I-C / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D007371:Interferon-gamma; D011070:Poly I-C