Science for Life Laboratory, Department of Immunology, Genetics and Pathology and.
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
J Clin Invest. 2024 Sep 10;134(21):e175310. doi: 10.1172/JCI175310.
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.
具有 MYCN 扩增的儿童神经母细胞瘤被归类为高危肿瘤，即使经过强化治疗后仍常常复发。针对 PD-1/L1 轴的免疫检查点阻断疗法在神经母细胞瘤患者中的疗效有限，且癌症内在免疫调节网络尚未被充分了解。在此，我们利用全基因组 CRISPR/Cas9 筛选鉴定出 H2AFY 是临床批准的 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，并与患者预后较差相关。在 MYCN 驱动的神经母细胞瘤细胞中遗传缺失 H2afy 可通过引发适应性和固有免疫的激活来逆转体内对 PD-1 阻断的耐药性。表观遗传学和翻译组学图谱的绘制表明，H2afy 缺失可促进细胞向间充质样状态转变。通过多组学方法，我们揭示了 H2AFY 相关基因在患者中具有功能相关性和预后意义。总之，我们的研究阐明了 H2AFY 作为高危神经母细胞瘤中细胞状态和免疫原性的表观遗传守门人的作用。
