1. A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.
- Author
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Hamilton AK, Radaoui AB, Tsang M, Martinez D, Conkrite KL, Patel K, Sidoli S, Delaidelli A, Modi A, Rokita JL, Lane MV, Hartnett N, Lopez RD, Zhang B, Zhong C, Ennis B, Miller DP, Brown MA, Rathi KS, Raman P, Pogoriler J, Bhatti T, Pawel B, Glisovic-Aplenc T, Teicher B, Erickson SW, Earley EJ, Bosse KR, Sorensen PH, Krytska K, Mosse YP, Havenith KE, Zammarchi F, van Berkel PH, Smith MA, Garcia BA, Maris JM, and Diskin SJ
- Subjects
- Humans, Animals, Cell Line, Tumor, Proteogenomics methods, Mice, Xenograft Model Antitumor Assays, Membrane Proteins genetics, Membrane Proteins metabolism, Immunotherapy methods, Gene Expression Regulation, Neoplastic, Cell Differentiation, Neuroblastoma genetics, Neuroblastoma immunology, Neuroblastoma therapy, Neuroblastoma metabolism, Neuroblastoma pathology, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism
- 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., Competing Interests: Declaration of interests F. Zammarchi, K. Havenith, and P.H.v.B. are or were employed by ADC Therapeutics at the time the work was conducted and hold or previously held shares/stocks in ADC Therapeutics. The following patent is held: WO2018146199A1., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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