title: TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells.
abstract: Acute lymphoblastic leukemia (ALL) still frequently recurs after hematopoietic stem cell transplantation (HSCT), underscoring the need to improve the graft-versus-leukemia (GvL) effect. Natural killer (NK) cells reconstitute in the first months following HSCT when leukemia burden is at its lowest, but ALL cells have been shown to be resistant to NK cell-mediated killing. We show here that this resistance is overcome by NK cell stimulation with TLR-9-activated plasmacytoid dendritic cells (pDCs). NK cell priming with activated pDCs resulted in TRAIL and CD69 up-regulation on NK cells and IFN-γ production. NK cell activation was dependent on IFN-α produced by pDCs, but was not reproduced by IFN-α alone. ALL killing was further enhanced by inhibition of KIR engagement. We showed that ALL lysis was mainly mediated by TRAIL engagement, while the release of cytolytic granules was involved when ALL expressed NK cell activating receptor ligands. Finally, adoptive transfers of activated-pDCs in ALL-bearing humanized mice delayed the leukemia onset and cure 30% of mice. Our data therefore demonstrate that TLR-9 activated pDCs are a powerful tool to overcome ALL resistance to NK cell-mediated killing and to reinforce the GvL effect of HSCT. These results open new therapeutic avenues to prevent relapse in children with ALL.
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.|Département de Microbiologie Infectiologie & Immunologie, Université de Montréal, Québec, Canada.
authors: Martin
authors: M
authors: Lelaidier
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.|Département de Microbiologie Infectiologie & Immunologie, Université de Montréal, Québec, Canada.
authors: Yildian
authors: Y
authors: Dìaz-Rodriguez
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.|Département de Microbiologie Infectiologie & Immunologie, Université de Montréal, Québec, Canada.
authors: Martine
authors: M
authors: Cordeau
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.
authors: Paulo
authors: P
authors: Cordeiro
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.|Département de Microbiologie Infectiologie & Immunologie, Université de Montréal, Québec, Canada.|Département de Pédiatrie, Université de Montréal, Québec, Canada.|Département de Sciences Biomédicales, Université de Montréal, Québec, Canada.
authors: Elie
authors: E
authors: Haddad
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.|Département de Pédiatrie, Université de Montréal, Québec, Canada.
authors: Sabine
authors: S
authors: Herblot
authors: Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montréal, Québec, Canada.|Département de Pédiatrie, Université de Montréal, Québec, Canada.|Département de Sciences Biomédicales, Université de Montréal, Québec, Canada.
authors: Michel
authors: M
authors: Duval
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D016923:Cell Death; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D006801:Humans; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D054340:Receptors, KIR / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016898:Interferon-alpha; D007371:Interferon-gamma; D037181:Lectins, C-Type; D054340:Receptors, KIR; D053221:TNF-Related Apoptosis-Inducing Ligand; D051217:Toll-Like Receptor 9; D000099192:CD69 Antigens; C573415:IFNG protein, human; C495371:TLR9 protein, human; C505653:TNFSF10 protein, human
keywords: TRAIL; interferon-alpha; natural killer cells; pediatric acute lymphoblastic leukemia; plasmacytoid dendritic cells