title: Efficient Killing of High Risk Neuroblastoma Using Natural Killer Cells Activated by Plasmacytoid Dendritic Cells.
abstract: High-risk neuroblastoma (NB) remains a major therapeutic challenge despite the recent advent of disialoganglioside (GD2)-antibody treatment combined with interleukin (IL)-2 and granulocyte monocyte-colony stimulating factor (GM-CSF). Indeed, more than one third of the patients still die from this disease. Here, we developed a novel approach to improve the current anti-GD2 immunotherapy based on NK cell stimulation using toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDCs). We demonstrated that this strategy led to the efficient killing of NB cells. When the expression of GD2 was heterogeneous on NB cells, the combination of pDC-mediated NK-cell activation and anti-GD2 treatment significantly increased the cytotoxicity of NK cells against NB cells. Activation by pDCs led to a unique NK-cell phenotype characterized by increased surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), with increased expression of CD69 on CD56dim cytotoxic cells, and strong interferon-γ production. Additionally, NB-cell killing was mediated by the TRAIL death-receptor pathway, as well as by the release of cytolytic granules via the DNAX accessory molecule 1 pathway. NK-cell activation and lytic activity against NB was independent of cell contact, depended upon type I IFN produced by TLR-9-activated pDCs, but was not reproduced by IFN-α stimulation alone. Collectively, these results highlighted the therapeutic potential of activated pDCs for patients with high-risk NB.
authors.affiliation: Groupe de Recherche En Transplantation et Immunologie du Sang de Cordon (GRETISC), Centre de cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Canada.|Department of Microbiology and Immunology, University of Montreal, Quebec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Cordeau
authors.affiliation: Groupe de Recherche En Transplantation et Immunologie du Sang de Cordon (GRETISC), Centre de cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Canada.|Department of Microbiology and Immunology, University of Montreal, Quebec, Canada.
authors.forename: Assila
authors.initials: A
authors.lastname: Belounis
authors.affiliation: Groupe de Recherche En Transplantation et Immunologie du Sang de Cordon (GRETISC), Centre de cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Canada.|Department of Microbiology and Immunology, University of Montreal, Quebec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Lelaidier
authors.affiliation: Groupe de Recherche En Transplantation et Immunologie du Sang de Cordon (GRETISC), Centre de cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Canada.
authors.forename: Paulo
authors.initials: P
authors.lastname: Cordeiro
authors.affiliation: Département d'anatomie et cytologie pathologiques CHU de Grenoble 38043 Grenoble Cedex 9, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.affiliation: Groupe de Recherche En Transplantation et Immunologie du Sang de Cordon (GRETISC), Centre de cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Canada.|Department of Pediatrics, University of Montreal, Quebec, Canada.
authors.forename: Sabine
authors.identifier: http://orcid.org/0000-0001-8702-7262
authors.initials: S
authors.lastname: Herblot
authors.affiliation: Groupe de Recherche En Transplantation et Immunologie du Sang de Cordon (GRETISC), Centre de cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Canada.|Department of Microbiology and Immunology, University of Montreal, Quebec, Canada.|Department of Pediatrics, University of Montreal, Quebec, Canada.|Department of Biomedical Sciences, University of Montreal, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Duval
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D019002:CD56 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009447:Neuroblastoma / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D016898:Interferon-alpha; D007371:Interferon-gamma; D037181:Lectins, C-Type; D053221:TNF-Related Apoptosis-Inducing Ligand; D051217:Toll-Like Receptor 9; D000099192:CD69 Antigens