A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma
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ABSTRACT: 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, the 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 71 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. Finally, we also found that DLK1 is highly expressed in several adult cancer types including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG) and small cell lung cancer (SCLC) suggesting potential clinical benefit beyond neuroblastoma. A clinical trial has been developed for evaluating ADCT-701 in neuroendocrine tumors in adults (https://www.clinicaltrials.gov/study/NCT06041516?term=adct-701&rank=1). Therefore, comprehensive characterization of cancer surfaceomes can provide biologically relevant immunotherapy targeting strategies.
INSTRUMENT(S): Orbitrap Fusion
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture
DISEASE(S): Neuroblastoma
SUBMITTER: Amber Weiner
LAB HEAD: Sharon Diskin
PROVIDER: PXD047474 | Pride | 2024-10-23
REPOSITORIES: Pride
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