Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target.

中文翻译：

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一项蛋白质基因组学表面组研究确定 DLK1 是神经母细胞瘤的免疫治疗靶点


癌症免疫疗法在 B 细胞恶性肿瘤中产生显着效果;然而，许多实体癌的最佳细胞表面靶标仍然难以捉摸。在这里，我们提出了肿瘤和正常组织的综合蛋白质组学、转录组学和表观基因组学分析，以确定神经母细胞瘤（一种通常致命的儿童癌症）的生物学相关细胞表面免疫治疗靶点。蛋白质基因组学分析揭示了 60 个高置信度的候选免疫治疗靶点，我们优先考虑 delta 样经典缺口配体 1 （DLK1） 进行进一步研究。DLK1 的高表达与超级增强子直接相关。免疫荧光、流式细胞术和免疫组织化学显示 DLK1 的细胞表面表达稳健。神经母细胞瘤细胞中短发夹 RNA 介导的 DLK1 沉默导致细胞分化增加。ADCT-701 是一种靶向 DLK1 的抗体-药物偶联物 （ADC），在表达 DLK1 的神经母细胞瘤异种移植模型中显示出有效和特异性的细胞毒性。由于在几种成人和儿童癌症中发现了高 DLK1 表达，我们的研究证明了蛋白质基因组学方法的效用，并将 DLK1 证明为免疫治疗靶点。