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 () and Charles Swanton ()
Additional contact information
Kevin Litchfield: The Francis Crick Institute
James L. Reading: University College London Cancer Institute
Emilia L. Lim: The Francis Crick Institute
Hang Xu: The Francis Crick Institute
Po Liu: The Francis Crick Institute
Maise Al-Bakir: The Francis Crick Institute
Yien Ning Sophia Wong: University College London Cancer Institute
Andrew Rowan: The Francis Crick Institute
Samuel A. Funt: Weill Cornell Medical College, and Parker Center for Cancer Immunotherapy
Taha Merghoub: Weill Cornell Medical College, and Parker Center for Cancer Immunotherapy
David Perkins: The Francis Crick Institute
Martin Lauss: Lund University
Inge Marie Svane: Copenhagen University Hospital Herlev
Göran Jönsson: Lund University
Javier Herrero: University College London Cancer Institute
James Larkin: The Royal Marsden Hospital
Sergio A. Quezada: University College London Cancer Institute
Matthew D. Hellmann: Weill Cornell Medical College, and Parker Center for Cancer Immunotherapy
Samra Turajlic: The Royal Marsden Hospital
Charles Swanton: The Francis Crick Institute

Nature Communications, 2020, vol. 11, issue 1, 1-11

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 (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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-17526-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17526-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-17526-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().