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Peer-reviewedCC BY-NC-NDCancer immunology, immunotherapy : CII

TRAIL orchestrates ThINKK-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia.

  • Émilie Ollame-Omvane1,2
  • Leila Ben Khemis1
  • Paulo Cordeiro1
  • Claire Fuchs1
  • Alex Richard-St-Hilaire1
  • Kathie Béland1
  • Elie Haddad1,2,3
  • Daniel Sinnett1,3
  • Sabine Herblot4,5
  • Michel Duval1,2,3
5 affiliations
  1. 1Centre de Cancérologie Charles-Bruneau, Centre de Recherche Azrieli du CHU Ste-Justine, Montréal, QC, Canada.
  2. 2Département d'Immunologie et Infectiologie, Université de Montréal, Montréal, QC, Canada.
  3. 3Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.
  4. 4Centre de Cancérologie Charles-Bruneau, Centre de Recherche Azrieli du CHU Ste-Justine, Montréal, QC, Canada. [email protected].
  5. 5Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada. [email protected].
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Abstract

Background: Therapeutic Inducers of Natural Killer cell Killing (ThINKK) 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 Natural Killer (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.

Methods: We performed NK cell cytotoxic assays using a panel of genetically diverse B-cell precursor ALL (BCP-ALL) cell lines and patients’ samples. We performed gene deletion and gene enforced expression in sensitive or resistant cell lines to investigate the role of TRAIL-receptors expression and death receptor-signaling pathway in BCP-ALL cell death induced 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 BCP-ALL patients from the CHU Sainte-Justine.

Results: We found that BCP‑ALL with diverse genetic backgrounds are sensitive to ThINKK‑stimulated NK‑cell killing. In addition, our data revealed the dual role of TRAIL: a strong NK cell-activating receptor that induced rapid killing of TRAIL-R2-expressing BCP-ALL through cytolytic granule release and cytokine secretion, and then, a death receptor–ligand inducing BCP-ALL apoptosis following sustained engagement with its receptors. The transcriptomic analysis of BCP-ALL patients’ samples indicated that TRAIL-R2 and TRAIL-R1 are widely expressed across BCP-ALL subtypes and are not downregulated at relapse.

Conclusion: These findings establish a mechanistic framework to guide patient stratification and therapeutic optimization.

Graphical abstract:

Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s00262-026-04502-z) contains supplementary material, which is available to authorized users.

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Cite

BibTeXRIS
BibTeX
@article{ollameomvane2026trail,
  title = {{TRAIL orchestrates ThINKK-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia.}},
  author = {Émilie Ollame-Omvane and Leila Ben Khemis and Paulo Cordeiro and Claire Fuchs and Alex Richard-St-Hilaire and Kathie Béland and Elie Haddad and Daniel Sinnett and Sabine Herblot and Michel Duval},
  journal = {Cancer immunology, immunotherapy : CII},
  year = {2026},
  month = aug,
  doi = {10.1007/s00262-026-04502-z},
  url = {https://europepmc.org/article/MED/42957925},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - TRAIL orchestrates ThINKK-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia.
AU  - Émilie Ollame-Omvane
AU  - Leila Ben Khemis
AU  - Paulo Cordeiro
AU  - Claire Fuchs
AU  - Alex Richard-St-Hilaire
AU  - Kathie Béland
AU  - Elie Haddad
AU  - Daniel Sinnett
AU  - Sabine Herblot
AU  - Michel Duval
PY  - 2026
DA  - 2026/08/03
JO  - Cancer immunology, immunotherapy : CII
DO  - 10.1007/s00262-026-04502-z
UR  - https://europepmc.org/article/MED/42957925
AB  - Background: Therapeutic Inducers of Natural Killer cell Killing (ThINKK) 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 Natural Killer (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.  Methods: We performed NK cell cytotoxic assays using a panel of genetically diverse B-cell precursor ALL (BCP-ALL) cell lines and patients’ samples. We performed gene deletion and gene enforced expression in sensitive or resistant cell lines to investigate the role of TRAIL-receptors expression and death receptor-signaling pathway in BCP-ALL cell death induced 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 BCP-ALL patients from the CHU Sainte-Justine.  Results: We found that BCP‑ALL with diverse genetic backgrounds are sensitive to ThINKK‑stimulated NK‑cell killing. In addition, our data revealed the dual role of TRAIL: a strong NK cell-activating receptor that induced rapid killing of TRAIL-R2-expressing BCP-ALL through cytolytic granule release and cytokine secretion, and then, a death receptor–ligand inducing BCP-ALL apoptosis following sustained engagement with its receptors. The transcriptomic analysis of BCP-ALL patients’ samples indicated that TRAIL-R2 and TRAIL-R1 are widely expressed across BCP-ALL subtypes and are not downregulated at relapse.  Conclusion: These findings establish a mechanistic framework to guide patient stratification and therapeutic optimization.  Graphical abstract:  Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s00262-026-04502-z) contains supplementary material, which is available to authorized users.
SN  - 0340-7004
SN  - 1432-0851
ER  -