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Escape from nonsens...
Escape from nonsense-mediated decay associates with anti-tumor immunogenicity
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- Litchfield, Kevin (author)
- Francis Crick Institute,University College London
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- Reading, James L. (author)
- University College London
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- Lim, Emilia L. (author)
- Francis Crick Institute
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- Xu, Hang (author)
- Francis Crick Institute
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- Liu, Po (author)
- Francis Crick Institute
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- Al-Bakir, Maise (author)
- Francis Crick Institute
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- Wong, Yien Ning Sophia (author)
- University College London
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- Rowan, Andrew (author)
- Francis Crick Institute
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- Funt, Samuel A. (author)
- Cornell University
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- Merghoub, Taha (author)
- Cornell University
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- Perkins, David (author)
- Francis Crick Institute
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- Lauss, Martin (author)
- Lund University,Lunds universitet,Melanoma Genomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Svane, Inge Marie (author)
- Herlev Hospital
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- Jönsson, Göran (author)
- Lund University,Lunds universitet,Melanoma Genomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Herrero, Javier (author)
- University College London
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- Larkin, James (author)
- Royal Marsden Hospital, London
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- Quezada, Sergio A. (author)
- University College London
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- Hellmann, Matthew D. (author)
- Memorial Sloan-Kettering Cancer Center,Cornell University
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- Turajlic, Samra (author)
- Royal Marsden Hospital, London,Francis Crick Institute
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- Swanton, Charles (author)
- University College London,Francis Crick Institute
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(creator_code:org_t)
- 2020-07-30
- 2020
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Litchfield, Kevi ...
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Reading, James L ...
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Lim, Emilia L.
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Xu, Hang
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Liu, Po
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Al-Bakir, Maise
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show more...
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Wong, Yien Ning ...
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Rowan, Andrew
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Funt, Samuel A.
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Merghoub, Taha
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Perkins, David
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Lauss, Martin
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Svane, Inge Mari ...
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Jönsson, Göran
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Herrero, Javier
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Larkin, James
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Quezada, Sergio ...
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Hellmann, Matthe ...
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Turajlic, Samra
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Swanton, Charles
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Nature Communica ...
- By the university
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Lund University