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

Autor: Paulo Cordeiro, Michel Duval, Sabine Herblot, Martin Lelaidier, Yildian Díaz-Rodríguez, Elie Haddad, Martine Cordeau
Rok vydání: 2015
Předmět:
Antigens
Differentiation
T-Lymphocyte
Cytotoxicity
Immunologic
Time Factors
interferon-alpha
medicine.medical_treatment
Cell
Priming (immunology)
TRAIL
Mice
SCID
Plasmacytoid dendritic cell
Hematopoietic stem cell transplantation
Biology
Lymphocyte Activation
Immunotherapy
Adoptive
Cell Degranulation
pediatric acute lymphoblastic leukemia
TNF-Related Apoptosis-Inducing Ligand
Interferon-gamma
Receptors
KIR
NK-92
Antigens
CD
Mice
Inbred NOD
Cell Line
Tumor
medicine
Animals
Humans
Lectins
C-Type
Interferon gamma
natural killer cells
Cell Death
hemic and immune systems
Dendritic Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
medicine.disease
Xenograft Model Antitumor Assays
Coculture Techniques
3. Good health
Killer Cells
Natural
Leukemia
Cytolysis
Phenotype
medicine.anatomical_structure
Oncology
plasmacytoid dendritic cells
Toll-Like Receptor 9
Immunology
Signal Transduction
Research Paper
medicine.drug
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: