A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.
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Weiner Amber K, Radaoui Alexander B, Tsang Matthew, Martinez Daniel, Sidoli Simone, Conkrite Karina L, Delaidelli Alberto, Modi Apexa, Rokita Jo Lynne, Patel Khushbu, Lane Maria V, Zhang Bo, Zhong Chuwei, Ennis Brian, Miller Daniel P, Brown Miguel A, Rathi Komal S, Raman Pichai, Pogoriler Jennifer, Bhatti Tricia, Pawel Bruce, Glisovic-Aplenc Tina, Teicher Beverly, Erickson Stephen W, Earley Eric J, Bosse Kristopher R, Sorensen Poul H, Krytska Kateryna, Mosse Yael P, Havenith Karin E, Zammarchi Francesca, van Berkel Patrick H, Smith Malcolm A, Garcia Benjamin A, Maris John M, Diskin Sharon J
Аннотация
UNLABELLED: Cancer immunotherapies have produced 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 specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target.
HIGHLIGHTS: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer DLK1 silencing in neuroblastoma cells results in cellular differentiation ADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models.