Escape from nonsense-mediated decay associates with anti-tumor immunogenicity

• DOI: 10.1038/s41467-020-17526-5
• Publication Date: 2020-07-30T10:24:08Z
• Authors: Kevin Litchfield; James L. Reading; Emilia L. Lim; Hang Xu; Po Liu; Maise Al-Bakir; Yien Ning Sophia ...; Andrew Rowan; Samuel A. Funt; Taha Merghoub; David Perkins; Martin Lauss; Inge Marie Svane; Göran Jönsson; Javier Herrero; James Larkin; Sergio A. Quezada; Matthew D. Hellmann; Samra Turajlic; Charles Swanton
• Keywords: Nonsense-Mediated Decay; Indel

Abstract Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype. Although fs-indels degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some escape degradation and elicit anti-tumor immune responses. Using allele-specific expression analysis, expressed enriched in genomic positions predicted to NMD, associated with higher protein expression, consistent (NMD-escape). Across four independent melanoma cohorts, NMD-escape mutations significantly clinical-benefit checkpoint inhibitor (CPI) therapy ( P meta = 0.0039). additionally found associate low-TMB setting. Furthermore, adoptive cell treated cohort, count is most significant biomarker clinical-benefit. Analysis of functional T reactivity screens from personalized vaccine studies shows direct evidence fs-indel derived neoantigens eliciting response, particularly those elongated neo open reading frames. represent attractive target for optimisation immunotherapy design.