TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells.

// Martin Lelaidier 1,2 , Yildian Diaz-Rodriguez 1,2 , Martine Cordeau 1,2 , Paulo Cordeiro 1 , Elie Haddad 1,2,3,4 , Sabine Herblot 1,3 and Michel Duval 1,3,4 1 Groupe de Recherche en Transplantation & Immunologie du Sang de Cordon (GRETISC), Centre Cancerologie Charles-Bruneau, Centre de recherche du CHU Sainte-Justine, Montreal, Quebec, Canada 2 Departement de Microbiologie Infectiologie & Immunologie, Universite de Montreal, Quebec, Canada 3 Departement de Pediatrie, Universite de Montreal, Quebec, Canada 4 Departement de Sciences Biomedicales, Universite de Montreal, Quebec, Canada Correspondence to: Sabine Herblot, email: // Keywords : pediatric acute lymphoblastic leukemia, natural killer cells, plasmacytoid dendritic cells, TRAIL, interferon-alpha Received : June 09, 2015 Accepted : July 12, 2015 Published : July 22, 2015 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.