Abstract：
Treatment strategies for paediatric neuroblastoma as well as many other cancers are limited by the unfavourable tumour microenvironment (TME). In this study, the TMEs of neuroblastoma were grouped by their genetic signatures into four distinct subtypes: immune enriched, immune desert, non-proliferative and fibrotic. An Immune Score and a Proliferation Score were constructed based on the molecular features of the subtypes to quantify the immune microenvironment or malignancy degree of cancer cells in neuroblastoma, respectively. The Immune Score correlated with a patient\'s response to immunotherapy; the Proliferation Score was an independent prognostic biomarker for neuroblastoma and proved to be more accurate than the existing clinical predictors. This double scoring system was further validated and the conserved molecular pattern associated with immune landscape and malignancy degree was confirmed. Axitinib and BI-2536 were confirmed as candidate drugs for neuroblastoma by the double scoring system. Both in vivo and in vitro experiments demonstrated that axitinib-induced pyroptosis of neuroblastoma cells activated anti-tumour immunity and inhibited tumour growth; BI-2536 induced cell cycle arrest at the S phase in neuroblastoma cells. The comprehensive double scoring system of neuroblastoma may predict prognosis and screen for therapeutic strategies which could provide personalized treatments.
摘要：
儿科神经母细胞瘤以及许多其他癌症的治疗策略受到不利的肿瘤微环境（TME）的限制。在这项研究中,神经母细胞瘤的TMEs根据其遗传特征分为四个不同的亚型：免疫富集，免疫沙漠，非增生性和纤维化。根据亚型的分子特征构建免疫评分和增殖评分，以量化神经母细胞瘤中癌细胞的免疫微环境或恶性程度。分别。免疫评分与患者对免疫疗法的反应相关；增殖评分是神经母细胞瘤的独立预后生物标志物，并且被证明比现有的临床预测因子更准确。进一步验证了该双重评分系统，并证实了与免疫景观和恶性程度相关的保守分子模式。通过双重评分系统，阿西替尼和BI-2536被确认为神经母细胞瘤的候选药物。体内和体外实验均表明，阿西替尼诱导的神经母细胞瘤细胞的焦亡激活了抗肿瘤免疫力并抑制了肿瘤生长；BI-2536在神经母细胞瘤细胞中诱导细胞周期停滞在S期。神经母细胞瘤的综合双重评分系统可以预测预后并筛选治疗策略，从而提供个性化治疗。
