RESUMEN
Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.
Asunto(s)
Neoplasias/genética , Neoplasias/inmunología , Empalme del ARN/genética , Animales , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Antígenos de Neoplasias/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Epítopos/inmunología , Etilenodiaminas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Hematopoyesis/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia , Inflamación/patología , Ratones Endogámicos C57BL , Péptidos/metabolismo , Isoformas de Proteínas/metabolismo , Pirroles/farmacología , Empalme del ARN/efectos de los fármacos , Sulfonamidas/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.