{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusion: These findings establish a mechanistic framework to guide patient stratification and therapeutic optimization.\n\nGraphical abstract:\n\nElectronic 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.",
  "abstract_shown": true,
  "affiliations": [
    "Centre de Cancérologie Charles-Bruneau, Centre de Recherche Azrieli du CHU Ste-Justine, Montréal, QC, Canada.",
    "Département d'Immunologie et Infectiologie, Université de Montréal, Montréal, QC, Canada.",
    "Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada.",
    "Centre de Cancérologie Charles-Bruneau, Centre de Recherche Azrieli du CHU Ste-Justine, Montréal, QC, Canada. sabine.herblot@umontreal.ca.",
    "Département de Pédiatrie, Université de Montréal, Montréal, QC, Canada. sabine.herblot@umontreal.ca."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Émilie Ollame-Omvane"
    },
    {
      "affs": [
        0
      ],
      "name": "Leila Ben Khemis"
    },
    {
      "affs": [
        0
      ],
      "name": "Paulo Cordeiro"
    },
    {
      "affs": [
        0
      ],
      "name": "Claire Fuchs"
    },
    {
      "affs": [
        0
      ],
      "name": "Alex Richard-St-Hilaire"
    },
    {
      "affs": [
        0
      ],
      "name": "Kathie Béland"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Elie Haddad"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Daniel Sinnett"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Sabine Herblot",
      "orcid": "0000-0001-8702-7262"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Michel Duval"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b3gch4cz8azk8.bib",
  "cited_by": 0,
  "doi": "10.1007/s00262-026-04502-z",
  "fulltext_url": "https://europepmc.org/articles/PMC13719959",
  "id": "b3gch4cz8azk8",
  "issns": [
    "0340-7004",
    "1432-0851"
  ],
  "landing_url": "https://europepmc.org/article/MED/42957925",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2403|Immune Cell Function and Interaction"
    ]
  ],
  "openalex": "W7172337789",
  "pdf_url": "https://europepmc.org/articles/PMC13719959?pdf=render",
  "pmcid": "PMC13719959",
  "pmid": "42957925",
  "published": "2026-08-03",
  "publisher": "Springer",
  "ris": "https://research.draconitic.com/paper/b3gch4cz8azk8.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:47Z",
      "native_id": "MED:42957925",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42957925"
    },
    {
      "first_seen": "2026-11-02T12:23:50Z",
      "native_id": "PMC13719959",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s00262-026-04502-z"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune Cell Function and Interaction",
      "subfield": "immunology"
    }
  ],
  "title": "TRAIL orchestrates ThINKK-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia.",
  "title_text": "TRAIL orchestrates ThINKK-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:55Z",
  "url": "https://research.draconitic.com/paper/b3gch4cz8azk8",
  "venue": "Cancer immunology, immunotherapy : CII",
  "versions": []
}