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, in part, through the influence of PRMT5 and E2F1 on RNA splicing and the presence of retained introns (RIs). We found that RIs have a propensity to form double-stranded RNAs that contribute to the innate response. Furthermore, many RIs contain non-canonical open-reading frames (ncORFs), 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, as 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 human 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 enhance tumour immunogenicity. PRMT5-regulated intron retention generates non-canonical MHC class I antigens that drive anti-tumour immunity and can be exploited for cancer vaccine development. PRMT5 was found to regulate retained intron (RI)-derived transcripts with the propensity to form double-stranded RNA that contribute to the innate interferon response. The identified retained introns were shown to contain non-canonical open reading frames that are translated and processed into MHC class I-presented peptides. A vaccine containing RI-derived peptides (PepMInt) was demonstrated to delay tumour growth and prolong survival in a syngeneic mouse model. T lymphocytes reactive to RI-derived peptides were detected in colorectal cancer patients and were shown to kill tumour cells in vitro. PRMT5 was found to regulate retained intron (RI)-derived transcripts with the propensity to form double-stranded RNA that contribute to the innate interferon response. The identified retained introns were shown to contain non-canonical open reading frames that are translated and processed into MHC class I-presented peptides. A vaccine containing RI-derived peptides (PepMInt) was demonstrated to delay tumour growth and prolong survival in a syngeneic mouse model. T lymphocytes reactive to RI-derived peptides were detected in colorectal cancer patients and were shown to kill tumour cells in vitro. PRMT5-regulated intron retention generates non-canonical MHC class I antigens that drive anti-tumour immunity and can be exploited for cancer vaccine development.