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

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posted on 05.08.2020 by Kevin Litchfield, James L Reading, Emilia L Lim, Hang Xu, Po Liu, Maise Al Bakir, Yien Ning Sophia Wong, 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
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.

Funding

Crick (Grant ID: 10169, Grant title: Swanton FC001169) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584) European Research Council (Grant ID: 617844 - THESEUS, Grant title: ERC 617844 - THESEUS) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) Cancer Research UK (Grant ID: C50947/A18176, Grant title: CRUK C50947/A18176)

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