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Abstract：
Neuroblastoma (NB) is a highly aggressive pediatric cancer that originates from immature nerve cells, presenting significant treatment challenges due to therapy resistance. Despite intensive treatment, approximately 50% of high-risk NB cases exhibit therapy resistance or experience relapse, resulting in poor outcomes often associated with tumor immune evasion. B7-H3 is an immune checkpoint protein known to inhibit immune responses. MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. Our study aims to explore the impact of miRNAs on B7-H3 regulation, the anti-tumor immune response, and tumorigenicity in NB. Analysis of NB patients and patient-derived xenograft tumors revealed a correlation between higher B7-H3 expression and poorer patient survival. Notably, deceased patients exhibited a depletion of miR-29 family members (miR-29a, miR-29b, and miR-29c), which displayed an inverse association with B7-H3 expression in NB patients. Overexpression and knockdown experiments demonstrated that these miRNAs degrade B7-H3 mRNA, resulting in enhanced NK cell activation and cytotoxicity. In vivo, experiments provided further evidence that miR-29 family members reduce tumorigenicity, macrophage infiltration, and microvessel density, promote infiltration and activation of NK cells, and induce tumor cell apoptosis. These findings offer a rationale for developing more effective combination treatments that leverage miRNAs to target B7-H3 in NB patients.
摘要：
神经母细胞瘤（NB）是一种高度侵袭性的儿科癌症，起源于未成熟的神经细胞，由于治疗抵抗，提出了重大的治疗挑战。尽管接受了强化治疗,大约50%的高危NB病例表现出治疗抵抗或复发，导致不良预后通常与肿瘤免疫逃避有关。B7-H3是已知抑制免疫应答的免疫检查点蛋白。微小RNA(miRNA)是参与转录后基因调控的非编码小RNA。我们的研究旨在探讨miRNAs对B7-H3调控的影响。抗肿瘤免疫反应，和NB的致瘤性。对NB患者和患者来源的异种移植肿瘤的分析显示，较高的B7-H3表达与较差的患者生存率之间存在相关性。值得注意的是,已故患者表现出miR-29家族成员的耗竭(miR-29a，miR-29b,和miR-29c），这与NB患者的B7-H3表达呈负相关。过表达和敲低实验表明，这些miRNA降解B7-H3mRNA，导致增强的NK细胞活化和细胞毒性。在体内,实验提供了进一步的证据，表明miR-29家族成员降低致瘤性，巨噬细胞浸润，和微血管密度，促进NK细胞的浸润和活化，诱导肿瘤细胞凋亡。这些发现为开发更有效的联合治疗提供了基本原理，该治疗利用miRNA靶向NB患者的B7-H3。
