Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome
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Roberto Vendramin Hongchang Fu Shanila FernandezPatel Yue Zhao Danwen Qian Lorena Ligammari Osnat Bartok Polina Greenberg Ronen Levy Andrea Castro Krupa Thakkar Jun Murai Wei-Ting Lu Christopher CT Sng Chen Weller Gordon Beattie Amandeep Bhamra Roc Farriol-Duran Despoina Karagianni Marcellus Augustine Krijn Dijkstra Christopher L Pinder Benjamin S Simpson Gordon Weng-Kit Cheung TRACERx Consortium

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Abstract

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.