Liao Yu-Mei, Hung Tsai-Hsien, Tung John K, Yu John, Hsu Ya-Ling, Hung Jung-Tung, Yu Alice L
Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
Program in Translational Medicine, Kaohsiung Medical University, Kaohsiung, and Academia Sinica, Taipei 115, Taiwan.
J Pers Med. 2021 Feb 13;11(2):122. doi: 10.3390/jpm11020122.
Immune tumor microenvironment (TME) in neuroblastoma (NBL) contributes to tumor behavior and treatment response. T cells and natural killer (NK) cells have been shown to play important roles in the neuroblastoma TME. However, few reports address the clinical relevance of natural killer T cells (NKTs) and interleukin-15 (IL-15), one of the crucial cytokines controlling the activation and expansion of NK/NKT cells, in NBL. In this study, we examined NKT immunoscores and IL-15 expression in both MYCN-amplified and MYCN-non-amplified NBL to correlate with clinical outcomes such as event-free survival (EFS) and overall survival (OS). From Gene Expression Omnibus (GEO) datasets GSE45480 ( = 643) and GSE49711 ( = 493), we found that NKT immunoscore and IL-15 expression were both significantly lower in MYCN-amplified NBL, and similar results were observed using our clinical NBL samples ( = 53). Moreover, NBL patients (GEO dataset GSE49711 and our clinical samples) with both lower NKT immunoscore and IL-15 expression exhibited decreased EFS and OS regardless of MYCN gene amplification status. Multivariate analysis further showed that the combination of low NKT immunoscore and low IL-15 expression level was an independent prognostic factor for poor EFS and OS in our NBL patients. These findings provide the rationale for the development of strategy to incorporate IL-15 and NKT cell therapy into the treatment regimen for neuroblastoma.
神经母细胞瘤（NBL）中的免疫肿瘤微环境（TME）影响肿瘤行为和治疗反应。T细胞和自然杀伤（NK）细胞已被证明在神经母细胞瘤TME中发挥重要作用。然而，关于自然杀伤T细胞（NKTs）和白细胞介素-15（IL-15）（控制NK/NKT细胞激活和扩增的关键细胞因子之一）在NBL中的临床相关性的报道很少。在本研究中，我们检测了MYCN扩增和MYCN未扩增的NBL中的NKT免疫评分和IL-15表达，以与无事件生存期（EFS）和总生存期（OS）等临床结果相关联。从基因表达综合数据库（GEO）数据集GSE45480（n = 643）和GSE49711（n = 493）中，我们发现MYCN扩增的NBL中NKT免疫评分和IL-15表达均显著降低，使用我们的临床NBL样本（n = 53）也观察到了类似结果。此外，无论MYCN基因扩增状态如何，NKT免疫评分和IL-15表达均较低的NBL患者（GEO数据集GSE49711和我们的临床样本）的EFS和OS均降低。多变量分析进一步表明，低NKT免疫评分和低IL-15表达水平的组合是我们NBL患者EFS和OS不良的独立预后因素。这些发现为将IL-15和NKT细胞疗法纳入神经母细胞瘤治疗方案的策略制定提供了理论依据。
