CoREST complex inhibition alters RNA splicing to promote neoantigen expression and enhance tumor immunity.

Epigenetic macromolecular enzyme complexes tightly regulate gene expression at the chromatin level and have recently been found to colocalize with RNA 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 (LSD1-HDAC1-CoREST) with components of the RNA splicing machinery and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM, we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex selective inhibitor, corin, leading to extensive changes in RNA splicing in melanoma and other malignancies. Moreover, these corin-induced splicing changes are shown to promote global effects on oncogenic and survival-associated splice variants, leading to a tumor-suppressive phenotype. Using machine learning models, MHC IP-MS, and ELISpot assays, we identify thousands of neopeptides derived from unannotated splice sites that generate corin-induced splice-neoantigens that are demonstrated to be immunogenic in vitro. Corin is further shown to reactivate the response to immune checkpoint blockade, effectively sensitizing tumors to anti-PD-1 immunotherapy. These data position CoREST complex inhibition as a unique therapeutic opportunity that perturbs oncogenic splicing programs while also creating tumor-associated neoantigens that enhance the immunogenicity of current therapeutics.