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

Litchfield, Kevin LU ; Reading, James L. ; Lim, Emilia L. ; Xu, Hang ; Liu, Po ; Al-Bakir, Maise ; Wong, Yien Ning Sophia ; Rowan, Andrew ; Funt, Samuel A. and Merghoub, Taha , et al. (2020) In Nature Communications 11(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
issue
1
article number
3800
publisher
Nature Publishing Group
external identifiers
  • pmid:32733040
  • scopus:85088796111
ISSN
2041-1723
DOI
10.1038/s41467-020-17526-5
language
English
LU publication?
yes
id
500b1e69-ddff-4e31-a216-89678fa416cc
date added to LUP
2020-08-07 10:57:04
date last changed
2024-04-17 14:01:54
@article{500b1e69-ddff-4e31-a216-89678fa416cc,
  abstract     = {{<p>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<sub>meta</sub> = 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.</p>}},
  author       = {{Litchfield, Kevin and Reading, James L. and Lim, Emilia L. and Xu, Hang and Liu, Po and Al-Bakir, Maise and Wong, Yien Ning Sophia and Rowan, Andrew and Funt, Samuel A. and Merghoub, Taha and Perkins, David and Lauss, Martin and Svane, Inge Marie and Jönsson, Göran and Herrero, Javier and Larkin, James and Quezada, Sergio A. and Hellmann, Matthew D. and Turajlic, Samra and Swanton, Charles}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Escape from nonsense-mediated decay associates with anti-tumor immunogenicity}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-17526-5}},
  doi          = {{10.1038/s41467-020-17526-5}},
  volume       = {{11}},
  year         = {{2020}},
}