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Litchfield, Kevin; Reading, James L; Lim, Emilia L; Xu, Hang; Liu, Po; Al-Bakir, Maise; Wong, Yien Ning Sophia; Rowan, Andrew; Funt, Samuel A; Merghoub, Taha; Perkins, David; Lauss, Martin; Svane, Inge Marie; Jönsson, Göran; Herrero, Javier; Larkin, James; Quezada, Sergio A; Hellmann, Matthew D; Turajlic, Samra; Swanton, Charles
Nature communications, 07/2020, Volume: 11, Issue: 1Journal Article
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 (P = 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.
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