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

Nat Commun. 2020 Jul 30;11(1):3800. doi: 10.1038/s41467-020-17526-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Antigens, Neoplasm / immunology
  • Biomarkers, Tumor / genetics
  • Exome Sequencing
  • Frameshift Mutation / genetics
  • Humans
  • INDEL Mutation / genetics
  • Immunotherapy, Adoptive
  • Melanoma / genetics*
  • Melanoma / immunology*
  • Nonsense Mediated mRNA Decay / genetics*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation
  • Tumor Escape / genetics*


  • Antigens, Neoplasm
  • Biomarkers, Tumor