Journal Article

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

Liu, Po, Litchfield, Kevin, Rowan, Andrew, Al-Bakir, Maise, Herrero, Javier, Reading, James L., Turajlic, Samra, Swanton, Charles, Lauss, Martin, Lim, Emilia L., Merghoub, Taha, Hellmann, Matthew D., Quezada, Sergio A., Funt, Samuel A., Jönsson, Göran, Xu, Hang, Perkins, David, Svane, Inge Marie, Wong, Yien Ning Sophia, Larkin, James

2020

Overview

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. The transcripts generated by frameshifts and indels in cancer are frequently degraded by nonsense mediated decay. Here, the authors show that some of these transcripts can escape this degradation mechanism and their prevalence correlates with tumour response to immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 45/91 / 631/67/1813 / 631/67/580 / 631/67/580/1884/2323 / 631/67/69 / 82/80 / Adoptive Transfer / Antigens, Neoplasm - immunology / Biomarkers / Biomarkers, Tumor - genetics / Cancer and Oncology / Cancer och onkologi / Cell therapy / Clinical Medicine / Decay / Degradation / Design optimization / Exome Sequencing / Frameshift Mutation - genetics / Genomics / Humanities and Social Sciences / Humans / Immune checkpoint / Immune response / Immune system / Immunogenicity / Immunotherapy / Immunotherapy, Adoptive / INDEL Mutation - genetics / Klinisk medicin / Lymphocytes / Lymphocytes T / Medical and Health Sciences / Medicin och hälsovetenskap / Melanoma / Melanoma - genetics / Melanoma - immunology / multidisciplinary / Mutation / Neoantigens / Nonsense Mediated mRNA Decay - genetics / Open reading frames / Science / Science (multidisciplinary) / T-Lymphocytes - immunology / T-Lymphocytes - transplantation / Tumor Escape - genetics / Tumors