Pharmacologic inhibition of nonsense-mediated decay induces anti-tumour immunogenicity in ex vivo patient tumours
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Roberto Vendramin Hongchang Fu Yue Zhao Shanila Fernandez Patel Danwen Qian Lorena Ligammari Ronen Levy Polina Greenberg Andrea Castro Krupa Thakkar Lisa Nguyen Gordon Beattie Jun Murai Despoina Karagianni Mansi Shah Petra Vlckova Manuel Rodriguez-Justo Christopher CT Sng Benjamin S Simpson Krijn K Djikstra Osnat Bartok Felipe Galvez-Cancino The TRACERx Consortium Eva Gronroos Stephen Dann Sergio A Quezada James Reading Yardena Samuels Charles Swanton Kevin Litchfield
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Abstract
Frameshift insertion/deletions are a key source of neoantigens. Frameshifted transcripts often contain premature termination codons and are degraded by the nonsense-mediated mRNA decay (NMD) pathway. Leveraging exome, transcriptome, and checkpoint inhibition response data from over 1,000 patients we identify an association between genetic loss or lower expression of the NMD mediator SMG1 with improved responses to immunotherapy. Pharmacological targeting of SMG1 in patient-derived tumour fragments results in activation and expansion of tumour-reactive CD8+ lymphocytes. Mechanistically, SMG1 inhibition increases the abundance of frameshifted transcripts and their HLA presentation, converting the neoepitope count from a low- to a high-TMB-like state without inducing mutations. Co-culture of CD8+ lymphocytes with patient-derived tumour organoids or tumour cells upon SMG1 inhibition induces NMD- and antigen-dependent T cell activation and tumour cell killing. Our findings, in a clinically relevant platform, highlight SMG1 inhibition as a novel immune-oncology approach to exploit an untapped source of highly immunogenic peptides.
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