Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome.
Vendramin R., Fu H., Fernandez Patel S., Zhao Y., Qian D., Ligammari L., Bartok O., Greenberg P., Levy R., Castro A., Thakkar K., Murai J., Lu W-T., Sng CCT., Weller C., Beattie G., Bhamra A., Farriol-Duran R., Karagianni D., Augustine M., Dijkstra KK., Pinder CL., Simpson BS., Cheung GW-K., TRACERx Consortium ., Galvez-Cancino F., Vlckova P., Surinova S., Rodriguez-Justo M., Shah M., McGranahan N., Carlton JG., Grönroos E., Reading JL., Samuels Y., Swanton C., Quezada SA., Litchfield K.
DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.