Nygrén Petra, Bouhlal Jonas, Jokinen Emmi, Forstén Sofia, Laajala Essi, Dias Diogo, Adnan-Awad Shady, Ianevski Aleksandr, Klievink Jay, Lähteenmäki Hanna, Kuusanmäki Heikki, Myllymäki Mikko, Kasanen Tiina, Saeed Khalid, Lee Dean A, Hjorth-Hansen Henrik, Aittokallio Tero, Dufva Olli, Mustjoki Satu
Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.
Blood. 2025 Apr 10;145(15):1670-1686. doi: 10.1182/blood.2024025286.
Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK-cell function with oncological drugs could improve NK-cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of >500 small-molecule compounds, to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified second mitochondrially derived activator of caspases (SMAC) mimetics as potent enhancers of NK-cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK-cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK-cell transition to an activated state and suppressed the expression of interferon gamma (IFN-γ) by NK cells, thus preventing IFN-γ-mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK-cell-mediated killing, with potential clinical applications especially in patients with advanced phase CML.
自然杀伤（NK）细胞已被证明是安全有效的免疫疗法，与慢性髓性白血病（CML）的良好治疗反应相关。用肿瘤药物增强NK细胞功能可以改善基于NK细胞的免疫疗法。在此，我们使用了一个由500多种小分子化合物组成的高通量药物筛选平台，系统地评估肿瘤药物对原发性NK细胞针对CML细胞的作用。我们确定了第二线粒体衍生的半胱天冬酶激活剂（SMAC）模拟物在细胞系和原发性患者样本中都是NK细胞细胞毒性的有效增强剂。相比之下，包括糖皮质激素和酪氨酸激酶抑制剂（如达沙替尼）在内的几类药物抑制了NK细胞的细胞毒性。单细胞RNA测序揭示了药物诱导的NK细胞和靶CML细胞的转录组变化。SMAC模拟物上调了NK细胞中NF-κB靶基因，这可能有助于增强它们的细胞毒性。抑制性药物地塞米松、达沙替尼和索拉非尼阻止NK细胞转变为激活状态，并抑制NK细胞分泌干扰素γ（IFN-γ），从而阻止IFN-γ介导的靶细胞转录组反应。总之，我们发现SMAC模拟物使癌细胞对NK细胞介导的杀伤敏感，具有潜在的临床应用价值，特别是在晚期CML患者中。
