In vitro differentiated plasmacytoid dendritic cells as a tool to induce anti-leukemia activity of natural killer cells

Yildian Díaz-Rodríguez,Sabine Herblot,Michel Duval,Paulo Cordeiro,Assila Belounis

doi:10.1007/s00262-017-2022-y

Yildian Díaz-Rodríguez, Sabine Herblot + Show 3 more

Open Access

https://doi.org/10.1007/s00262-017-2022-y

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Abstract

Acute lymphoblastic leukemia (ALL) is believed to be resistant to NK cell-mediated killing. To overcome this resistance, we developed an innovative approach based on NK cell stimulation with Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC). The translation of this approach into the clinic requires the production of high numbers of human pDC. Herein, we show that in vitro differentiation of cord blood CD34+ progenitors in the presence of aryl hydrocarbon receptor antagonists gives rise to clinically relevant numbers of pDC, as about 108 pDC can be produced from a typical cord blood unit. Blocking the aryl hydrocarbon receptor (AHR) pathway significantly increased the yield of pDC. When compared to pDC isolated from peripheral blood, in vitro differentiated pDC (ivD-pDC) exhibited an increased capacity to induce NK cell-mediated killing of ALL. Although ivD-pDC produced lower amounts of IFN-α than peripheral blood pDC upon TLR activation, they produced more IFN-λ2, known to play a critical role in the induction of anti-tumoral NK cell functions. Both TLR-9 and TLR-7 ligands triggered pDC-induced NK cell activation, offering the possibility to use any clinical-grade TLR-7 or TLR-9 ligands in future clinical trials. Finally, adoptive transfer of ivD-pDC cultured in the presence of an AHR antagonist cured humanized mice with minimal ALL disease. Collectively, our results pave the way to clinical-grade production of sufficient numbers of human pDC for innate immunotherapy against ALL and other refractory malignancies.

Highlights

In the last decade, immunotherapy has been considered a major breakthrough in the field of anti-cancer therapy, since this approach demonstrated its efficacy against chemotherapy refractory cancers
We recently revealed that co-culture of resting natural killer (NK) cells with Toll-like receptor (TLR)-9-activated plasmacytoid dendritic cells (pDC) overcame the resistance of acute lymphoblastic leukemia (ALL) to NK cell killing
Since the induction of differentiation programs may interfere with the cellular functions of in vitro generated cells, we aimed to assess the functional properties of human in vitro differentiated pDC (ivD-pDC) obtained in the absence or in the presence of aryl hydrocarbon receptor (AHR) antagonists (CH223191 and StemRegenin-1—SR1)

Summary

Introduction

Immunotherapy has been considered a major breakthrough in the field of anti-cancer therapy, since this approach demonstrated its efficacy against chemotherapy refractory cancers. NK cells recognize and kill infected or transformed cells without prior sensitization [3] Their cytotoxicity activity against cancer cells is highly regulated by the balance between activating and inhibitory signals as well as their education in order to distinguish self and untransformed cells from cancer and infected cells. Cancer cells can become resistant to NK cell-mediated lysis by down-regulating ligands for NK cell activating receptors To circumvent this resistance, NK cell stimulation is required to increase the cytotoxic functions of NK cells [4]. We recently demonstrated that Toll-like receptor (TLR)-activated pDC induce a unique NK cell phenotype that could not be reproduced by IFN-α alone [12] This phenotype is characterized by a high expression of TNF-related apoptosis-inducing ligand (TRAIL) on the cell surface

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