Escape from nonsense-mediated decay associates with anti-tumor immunogenicity Journal Article
| Authors: | Litchfield, K.; Reading, J. L.; Lim, E. L.; Xu, H.; Liu, P.; Al-Bakir, M.; Wong, Y. N. S.; Rowan, A.; Funt, S. A.; Merghoub, T.; Perkins, D.; Lauss, M.; Svane, I. M.; Jönsson, G.; Herrero, J.; Larkin, J.; Quezada, S. A.; Hellmann, M. D.; Turajlic, S.; Swanton, C. |
| Article Title: | Escape from nonsense-mediated decay associates with anti-tumor immunogenicity |
| Abstract: | Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype. Although fs-indels are degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and elicit anti-tumor immune responses. Using allele-specific expression analysis, expressed fs-indels are enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (NMD-escape). Across four independent melanoma cohorts, NMD-escape mutations are significantly associated with clinical-benefit to checkpoint inhibitor (CPI) therapy (Pmeta = 0.0039). NMD-escape mutations are additionally found to associate with clinical-benefit in the low-TMB setting. Furthermore, in an adoptive cell therapy treated melanoma cohort, NMD-escape mutation count is the most significant biomarker associated with clinical-benefit. Analysis of functional T cell reactivity screens from personalized vaccine studies shows direct evidence of fs-indel derived neoantigens eliciting immune response, particularly those with highly elongated neo open reading frames. NMD-escape fs-indels represent an attractive target for biomarker optimisation and immunotherapy design. © 2020, The Author(s). |
| Keywords: | protein expression; sequence analysis; frameshift mutation; mass spectrometry; ipilimumab; melanoma; gene expression; gene frequency; inhibitor; immunoreactivity; immune response; immunotherapy; microsatellite instability; cell therapy; immunoassay; tumor; cutaneous melanoma; indel mutation; nonsense mediated mrna decay; tumor immunogenicity; dna sequencing; human; article; rna sequencing; checkpoint kinase inhibitor; whole exome sequencing; mutational load; whole transcriptome sequencing; antitumor immunogenicity |
| Journal Title: | Nature Communications |
| Volume: | 11 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-07-30 |
| Start Page: | 3800 |
| Language: | English |
| DOI: | 10.1038/s41467-020-17526-5 |
| PUBMED: | 32733040 |
| PROVIDER: | scopus |
| PMCID: | PMC7393139 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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