van Vliet Amanda A, van den Hout Mirjam G C N, Steenmans Daniëlle, Duru Adil D, Georgoudaki Anna-Maria, de Gruijl Tanja D, van IJcken Wilfred F J, Spanholtz Jan, Raimo Monica
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands.
Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
Mol Ther Oncol. 2024 Sep 2;32(4):200870. doi: 10.1016/j.omton.2024.200870. eCollection 2024 Dec 19.
Allogeneic natural killer (NK) cell therapies are a valuable treatment option for cancer, given their remarkable safety and favorable efficacy profile. Although the use of allogeneic donors allows for off-the-shelf and timely patient treatment, intrinsic interindividual differences put clinical efficacy at risk. The identification of donors with superior anti-tumor activity is essential to ensure the success of adoptive NK cell therapies. Here, we investigated the heterogeneity of 10 umbilical cord blood stem cell-derived NK cell batches. First, we evaluated the donors' cytotoxic potential against tumor cell lines from solid and hematological cancer indications, to distinguish a group of superior, "excellent" killers (4/10), compared with "good" killers (6/10). Next, bulk and single-cell RNA sequencing, performed at different stages of NK differentiation, revealed distinct transcriptomic features of the two groups. Excellent donors showed an enrichment in cytotoxicity pathways and a depletion of myeloid traits, linked to the presence of a larger population of effector-like NK cells early on during differentiation. Consequently, we defined a multi-factorial gene expression signature able to predict the donors' cytotoxic potential. Our study contributes to the identification of key traits of superior NK cell batches, supporting the development of efficacious NK therapeutics and the achievement of durable anti-tumor responses.
同种异体自然杀伤（NK）细胞疗法因其卓越的安全性和良好的疗效，是一种有价值的癌症治疗选择。尽管使用同种异体供体可实现即现货供应并及时为患者进行治疗，但个体间的内在差异会使临床疗效面临风险。识别具有卓越抗肿瘤活性的供体对于确保过继性NK细胞疗法的成功至关重要。在此，我们研究了10个脐带血干细胞来源的NK细胞批次的异质性。首先，我们评估了供体对实体瘤和血液系统癌症来源的肿瘤细胞系的细胞毒性潜力，以区分出一组卓越的“优秀”杀伤者（4/10），并与“良好”杀伤者（6/10）进行比较。接下来，在NK细胞分化的不同阶段进行的批量和单细胞RNA测序揭示了两组不同的转录组特征。优秀的供体在细胞毒性途径方面表现出富集，而髓系特征则减少，这与分化早期存在大量效应样NK细胞有关。因此，我们定义了一个能够预测供体细胞毒性潜力的多因素基因表达特征。我们的研究有助于识别卓越NK细胞批次的关键特征，支持有效的NK治疗药物的开发以及实现持久的抗肿瘤反应。
