PXD047474-1

PXD047474 is an original dataset announced via ProteomeXchange.

Title	A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-23
AnnouncementXML	Submission_2024-10-23_13:36:03.328.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Amber Weiner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-03 10:51:05	ID requested
⏵ 1	2024-10-23 13:36:03	announced

10.1016/J.CCELL.2024.10.003;

submitter keyword: neuroblastoma, antibody-drug conjugate, mass spectrometry, immunotherapy,cancer, DLK1, surfaceome

Sharon Diskin
contact affiliation	Children's Hospital of Philadelphia
contact email	diskin@chop.edu
lab head
Amber Weiner
contact affiliation	Childrens Hospital of Philadelphia
contact email	weinera@chop.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047474
     1. Label: PRIDE project
     2. Name: A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma