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

Oncotarget
Martin LelaidierMichel Duval

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 HSC...Continue Reading

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Citations

May 31, 2017·Cancer Immunology, Immunotherapy : CII·Yildian Díaz-RodríguezMichel Duval
Oct 3, 2019·Cancers·Duygu SagGerhard Wingender
Jan 12, 2019·Frontiers in Immunology·Wei Du, Xuefang Cao
Jul 28, 2020·Progress in Retinal and Eye Research·Arsia JamaliPedram Hamrah
Jan 28, 2021·Cancers·Vicky Mengfei QinJoe Jiang Zhu
Jun 15, 2021·Journal of Immunology Research·Saghar PahlavanneshanMohsen Basiri

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Methods Mentioned

BETA
flow
ELISA
flow cytometry
PCR
density gradient centrifugation
Assay
enzyme-linked immunosorbent assay
X-ray

Software Mentioned

FlowJo

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