PRMT5-mediated intron retention triggers innate and adaptive immunity against cancer

PRMT5 is expressed at high levels in many cancers, where it regulates diverse cellular pathways that contribute to oncogenesis. Here, we have defined a new role for PRMT5 in regulating and coordinating the interplay between the innate and adaptive immune response. This occurs through the influence of PRMT5 on RNA splicing and the presence of retained introns (RIs). We found that RIs, which occur upon PRMT5 inhibition, have a propensity to form double-stranded RNA structures which activate the innate immune response. Furthermore, many RIs contain cryptic open reading frames which can be translated and then processed into small peptides that assemble with the MHC class I complex. Significantly, RI-derived peptides are highly immunogenic and a murine cancer vaccine, carrying a string of antigenic RI peptides, delayed tumour growth and enhanced survival. RIs are present in human tumour cells, and we identified T lymphocytes in cancer patients with antigen specificity for RI-derived peptides that killed human tumour cells in vitro. Regulating intron retention thus offers a new therapeutic approach to regulate tumour immunogenicity.