近日，美国费城儿童医院教授Sharon J. Diskin及其研究组发现，一项蛋白质组学表面组研究确定了DLK1作为神经母细胞瘤的免疫治疗靶点。相关论文于2024年10月25日在线发表在《癌细胞》杂志上。

研究人员展示了对肿瘤和正常组织进行的综合蛋白质组学、转录组学和表观基因组学分析，以识别神经母细胞瘤（这种常常致命的儿童癌症）的生物相关细胞表面免疫治疗靶点。蛋白质组学分析揭示了六十个高可信度的候选免疫治疗靶点，研究人员优先选择了DLK1（delta-like canonical notch ligand 1）进行进一步研究。

DLK1的高表达与超增强子直接相关。免疫荧光、流式细胞术和免疫组织化学显示DLK1在细胞表面的强表达。通过短发夹RNA介导的DLK1沉默处理神经母细胞瘤细胞会导致细胞分化增加。针对DLK1的抗体-药物结合物（ADC）ADCT-701在表达DLK1的神经母细胞瘤异种移植模型中显示出强效且特异的细胞毒性。

由于在几种成人和儿童癌症中发现高表达的DLK1，该研究展示了蛋白质组学方法的实用性，并确认了DLK1作为免疫治疗靶点的潜力。

据介绍，癌症免疫疗法在B细胞恶性肿瘤中取得了显著成果；然而，许多实体癌症的最佳细胞表面靶点仍然难以确定。

附：英文原文

Title: A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma

Author: Amber K. Hamilton, Alexander B. Radaoui, Matthew Tsang, Daniel Martinez, Karina L. Conkrite, Khushbu Patel, Simone Sidoli, Alberto Delaidelli, Apexa Modi, Jo Lynne Rokita, Maria V. Lane, Nicholas Hartnett, Raphael D. Lopez, Bo Zhang, Chuwei Zhong, Brian Ennis, Daniel P. Miller, Miguel A. Brown, Komal S. Rathi, Pichai Raman, Jennifer Pogoriler, Tricia Bhatti, Bruce Pawel, Tina Glisovic-Aplenc, Beverly Teicher, Stephen W. Erickson, Eric J. Earley, Kristopher R. Bosse, Poul H. Sorensen, Kateryna Krytska, Yael P. Mosse, Karin E. Havenith, Francesca Zammarchi, Patrick H. van Berkel, Malcolm A. Smith, Benjamin A. Garcia, John M. Maris, Sharon J. Diskin

Issue&Volume: 2024-10-25

Abstract: 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.

DOI: 10.1016/j.ccell.2024.10.003

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00366-0