PXD056700

PXD056700 is an original dataset announced via ProteomeXchange.

Title	CoREST Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity
Description	Epigenetic mechanisms tightly regulate gene expression at the chromatin level and have recently been found to colocalize with the splicing machinery during active transcription; however, the precise functional consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex with the RNA splicing machinery and their functional consequences. Using mass spectrometry, in vivo binding assays, and Cryo-EM we find that CoREST-splicing factor interactions are direct and perturbed by the bivalent inhibitor, corin, leading to robust changes in RNA splicing in melanoma and other malignancies. Moreover, these corin-associated splicing changes are shown to promote global effects on oncogenic and survival-associated splice variants leading to a tumor-suppressive phenotype. Using predictive machine learning models, MHC IP-MS, and ELISpot assays we identify thousands of neopeptides derived from unannotated splice sites which generate corin-induced splice neoantigens that are demonstrated to be immunogenic in vitro. Corin is further shown to inhibit tumor growth and enhance checkpoint blockade in a manner dependent on host T cells that trigger an anti-tumor T cell response in vivo and promote dramatic expansion of cytotoxic T cells in an immune cold melanoma tumor model, effectively sensitizing them to anti-PD1 immunotherapy. These data position CoREST inhibition as a unique therapeutic opportunity in cancer which reverses oncogenic splicing programs across broad tumor types while also creating tumor-associated neoantigens which may enhance the immunogenicity of current therapeutics and may be readily translated to the clinic.
HostingRepository	PRIDE
AnnounceDate	2025-11-10
AnnouncementXML	Submission_2025-11-10_10:01:07.225.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simone Sidoli
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-10 13:25:45	ID requested
⏵ 1	2025-11-10 10:01:07	announced

Dataset with its publication pending

submitter keyword: Melanoma,CoREST, RNA splicing, Cryo-EM, Immunotherapy, Neoantigens

Simone Sidoli
contact affiliation	Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, United States
contact email	simone.sidoli@einsteinmed.edu
lab head
Simone Sidoli
contact affiliation	Albert Einstein College of Medicine
contact email	simone.sidoli@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/11/PXD056700

PRIDE project URI

• PRIDE
  1. PXD056700
     1. Label: PRIDE project
     2. Name: CoREST Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity