Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder, Room 300, Birmingham, AL, 35233, UK.
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
Cancer Immunol Immunother. 2024 Sep 5;73(11):221. doi: 10.1007/s00262-024-03818-y.
Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death.
We utilized MYCN amplified and non-amplified neuroblastoma cell lines, the IL-12 expressing oHSV, M002, and the human NK cell line, NK-92 MI. We assessed the cytotoxicity of NK cells against neuroblastoma with and without M002 infection, the effects of M002 on NK cell priming, and the impact of M002 and priming on the migratory capacity and CD107a expression of NK cells. To test clinical applicability, we then investigated the effects of M002 and NK cells on neuroblastoma in vivo.
NK cells were more attracted to neuroblastoma cells that were infected with M002. There was an increase in neuroblastoma cell death with the combination treatment of M002 and NK cells both in vitro and in vivo. Priming the NK cells enhanced their cytotoxicity, migratory capacity and CD107a expression.
To the best of our knowledge, these investigations are the first to demonstrate the effects of an oncolytic virus combined with self-maintaining NK cells in neuroblastoma and the priming effect of neuroblastoma on NK cells. The current studies provide a deeper understanding of the relation between NK cells and neuroblastoma and these data suggest that oHSV increases NK cell cytotoxicity towards neuroblastoma.
神经母细胞瘤是儿童中最常见的颅外实体瘤，占儿童癌症相关死亡人数的 15%。由于肿瘤微环境中免疫细胞数量较少以及神经母细胞瘤肿瘤细胞释放免疫抑制细胞因子，用免疫疗法靶向神经母细胞瘤一直具有挑战性。我们假设，将溶瘤单纯疱疹病毒（oHSV）与自然杀伤（NK）细胞联合使用可能克服这些障碍并引发肿瘤细胞死亡。
我们利用 MYCN 扩增和非扩增神经母细胞瘤细胞系、表达白细胞介素 12 的 oHSV（M002）和人类 NK 细胞系 NK-92MI。我们评估了 NK 细胞在有无 M002 感染的情况下对神经母细胞瘤的细胞毒性、M002 对 NK 细胞的启动作用以及 M002 和启动作用对 NK 细胞迁移能力和 CD107a 表达的影响。为了测试临床适用性，我们随后研究了 M002 和 NK 细胞对体内神经母细胞瘤的影响。
感染 M002 的神经母细胞瘤细胞对 NK 细胞更具吸引力。在体外和体内，M002 和 NK 细胞联合治疗均增加了神经母细胞瘤细胞的死亡。NK 细胞的启动增强了其细胞毒性、迁移能力和 CD107a 表达。
据我们所知，这些研究首次证明了溶瘤病毒与自我维持的 NK 细胞联合用于神经母细胞瘤的效果，以及神经母细胞瘤对 NK 细胞的启动作用。目前的研究提供了对 NK 细胞与神经母细胞瘤之间关系的更深入了解，这些数据表明 oHSV 增加了 NK 细胞对神经母细胞瘤的细胞毒性。
