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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer
We explored the activating pathways involved in Natural killer (NK) cell activation by Toll-like receptors (TLRs)-9 activated plasmacytoid dendritic cells (pDCs) as well as the cytolytic pathways involved in ALL lysis
We showed that the stimulation of NK cells by TLR9-activated pDCs overcomes the resistance of ALL cells to NK cell-mediated killing
Summary
Despite progress in chemotherapy and hematopoietic stem cell transplantation (HSCT), ALL remains a leading cause of death by cancer in children [1]. One of the most promising avenues of research is the increase of the graft-versusleukemia (GvL) effect post-HSCT by harnessing the donor-derived immune system to eradicate leukemia. Natural killer (NK) cells are the first lymphocytes to recover following allogeneic HSCT, when the residual leukemic burden is at its lowest [4,5,6]. As innate cytotoxic lymphocytes able to recognize and eliminate infected or tumor cells without prior sensitization, NK cells play a major role in the GvL effect post-HSCT [7]. NK cells express several activating receptors including the C-type lectin NKG2D, the DNAX accessory molecule-1 (DNAM-1) and natural cytotoxicity receptors (NCRs) such as NKp30, NKp44 and NKp46. NK cell www.impactjournals.com/oncotarget cytotoxic activity can be further enhanced by cytokine stimulation, such as type I interferons (IFN) or by interactions with activated dendritic cells [11]
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