Scholarlink

Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>These findings establish a mechanistic framework to guide patient stratification and therapeutic optimization.</p> Graphical abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月3日

查看全文
  • Émilie Ollame-Omvane,
  • Leila Ben Khemis,
  • Paulo Cordeiro,
  • Claire Fuchs,
  • Alex Richard-St-Hilaire,
  • Kathie Béland,
  • Elie Haddad,
  • Daniel Sinnett,
  • Sabine Herblot,
  • Michel Duval

摘要

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