背景:神经母细胞瘤是儿童中最常见的颅外实体瘤,占儿科癌症相关死亡的15%。由于肿瘤微环境中免疫细胞的缺乏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已被证明具有挑战性。我们假设将溶瘤性单纯疱疹病毒(oHSV)与自然杀伤(NK)细胞结合可能会克服这些障碍并引起肿瘤细胞死亡。
方法:我们利用MYCN扩增和非扩增神经母细胞瘤细胞系,表达oHSV的IL-12,M002和人类NK细胞系,NK-92MI。我们评估了NK细胞对有和没有M002感染的神经母细胞瘤的细胞毒性,M002对NK细胞启动的影响,以及M002和引发对NK细胞迁移能力和CD107a表达的影响。为了测试临床适用性,然后我们在体内研究了M002和NK细胞对神经母细胞瘤的影响。
结果:NK细胞更容易被M002感染的神经母细胞瘤细胞所吸引。M002和NK细胞的联合治疗在体外和体内都增加了神经母细胞瘤细胞死亡。启动NK细胞增强了它们的细胞毒性,迁移能力和CD107a表达。
结论:据我们所知,这些研究首次证明溶瘤病毒联合自我维持NK细胞在神经母细胞瘤中的作用以及神经母细胞瘤对NK细胞的启动作用.当前的研究提供了对NK细胞与神经母细胞瘤之间关系的更深入理解,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。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.