CoREST Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skin

SUBMITTER: Simone Sidoli  

LAB HEAD: Simone Sidoli

PROVIDER: PXD056700 | Pride | 2025-11-10

REPOSITORIES: Pride