Childhood neuroblastoma with MYCN amplification is classified as high risk and often relapses after intensive treatments. Immune checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in patients with neuroblastoma, and the cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody nivolumab. Analysis of single-cell RNA-Seq datasets reveals that H2AFY mRNA is enriched in adrenergic cancer cells and is associated with worse patient survival. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverts in vivo resistance to PD-1 blockade by eliciting activation of the adaptive and innate immunity. Mapping of the epigenetic and translational landscape demonstrates that H2afy deletion promotes cell transition to a mesenchymal-like state. With a multiomics approach, we uncovered H2AFY-associated genes that are functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell states and immunogenicity in high-risk neuroblastoma.

中文翻译：

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H2AFY 对细胞状态的表观遗传调控控制高危神经母细胞瘤的免疫原性


MYCN 扩增的儿童神经母细胞瘤被归类为高风险，通常在强化治疗后复发。针对 PD-1/L1 轴的免疫检查点阻断疗法对神经母细胞瘤患者的疗效有限，并且对癌症内在免疫调节网络知之甚少。在这里，我们利用全基因组 CRISPR/Cas9 筛选，并将 H2AFY 确定为对临床批准的 PD-1 阻断抗体 nivolumab 的耐药基因。单细胞 RNA-Seq 数据集的分析表明，H2AFY mRNA 在肾上腺素能癌细胞中富集，与较差的患者生存率相关。MYCN 驱动的神经母细胞瘤细胞中 H2afy 的基因缺失通过引发适应性免疫和先天免疫的激活来恢复体内对 PD-1 阻断的耐药性。表观遗传学和翻译景观的图谱表明，H2afy 缺失促进细胞过渡到间充质样状态。通过多组学方法，我们发现了 H2AFY 相关基因，这些基因在患者中具有功能相关性和预后性。总而言之，我们的研究阐明了 H2AFY 作为高危神经母细胞瘤细胞状态和免疫原性的表观遗传守门人的作用。