Escape from nonsense-mediated decay associates with anti-tumor immunogenicity
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
Abstract
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 ( P meta = 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.