Therapeutic Inducers of NK cell Killing (ThINKK)-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia: unraveling the dual role of TRAIL leads to the establishment of an efficacy biomarker
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Background
Therapeutic Inducers of Natural Killer cell Killing represent a novel class of immunotherapy designed to enhance the graft-versus-leukemia effect of hematopoietic stem cell transplantation in pediatric patients with high-risk or relapse leukemia. Our previous work identified high expression of TRAIL as a key signature of NK cell stimulation by ThINKK. In this study, we aim to elucidate the mechanisms underlying acute lymphoblastic leukemia (ALL) killing by ThINNK-stimulated NK cells and to identify predictive sensitivity markers of this innovative approach.
Methods
We performed NK cell cytotoxic assays using a panel of genetically diverse ALL cell lines and patients’ samples. Gene deletion and gene enforced expression in sensitive or resistant cell lines were performed to demonstrate the role of TRAIL-R2 expression and death receptor signaling pathway in ALL killing by ThINKK-stimulated NK cells. These findings were further validated through the analysis of primary patients’ samples and transcriptomic profiling of a cohort of 320 ALL patients from the CHU Sainte-Justine.
Results
We found that ALL sensitivity to ThINKK-stimulated NK cell killing was independent of their genetic background or their expression of HLA. In addition, our data revealed the dual role of TRAIL: first, a strong NK cell activating receptor that induced rapid killing of ALL expressing TRAIL-R2, and second, a death-receptor ligand inducing ALL apoptosis following sustained engagement with its receptors. The transcriptomic analysis of ALL patients’ samples indicated that TRAIL-R2 and TRAIL-R1 are widely expressed across ALL subtypes and are not downregulated at relapse.
Conclusion
These data establish the expression of either TRAIL-R1 or TRAIL-R2 as a biomarker of sensitivity to ThINKK immunotherapy. This important insight provides a mechanistic basis for patient stratification and therapeutic optimization.
