Escape from nonsense-mediated decay associates with anti-tumor immunogenicity.
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Embargo End Date
ICR Authors
Authors
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, C
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, C
Document Type
Journal Article
Date
2020-07-30
Date Accepted
2020-06-30
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.
Citation
Nature Communications, 2020, 11 (1), pp. 3800 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723