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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Litchfield K,Reading JL,Lim EL,Xu H,Liu P,Al-Bakir M,Wong YNS,Rowan A,Funt SA,Merghoub T,Perkins D,Lauss M,Svane IM,Jönsson G,Herrero J,Larkin J,Quezada SA,Hellmann MD,Turajlic S,Swanton Cdoi
10.1038/s41467-020-17526-5subject
Has Abstractpub_date
2020-07-30 00:00:00pages
3800issue
1issn
2041-1723pii
10.1038/s41467-020-17526-5journal_volume
11pub_type
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