文章基本信息

标题：NMD inhibition by 5-azacytidine augments presentation of immunogenic frameshift-derived neoepitopes
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作者：Jonas P. Becker ; Dominic Helm ; Mandy Rettel 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：4
页码：1-52
DOI：10.1016/j.isci.2021.102389
语种：English
出版社：Elsevier
摘要：SummaryFrameshifted protein sequences elicit tumor-specific T cell-mediated immune responses in microsatellite-unstable (MSI) cancers if presented by HLA class I molecules. However, their expression and presentation are limited by nonsense-mediated RNA decay (NMD). We employed an unbiased immunopeptidomics workflow to analyze MSI HCT-116 cells and identified >10,000 HLA class I-presented peptides including five frameshift-derived InDel neoepitopes. Notably, pharmacological NMD inhibition with 5-azacytidine stabilizes frameshift-bearing transcripts and increases the HLA class I-mediated presentation of InDel neoepitopes. The frameshift mutation underlying one of the identified InDel neoepitopes is highly recurrent in MSI colorectal cancer cell lines and primary patient samples, and immunization with the corresponding neoepitope induces strong CD8+T cell responses in an HLA-A∗02:01 transgenic mouse model. Our data show directly that pharmacological NMD inhibition augments HLA class I-mediated presentation of immunogenic frameshift-derived InDel neoepitopes thus highlighting the clinical potential of NMD inhibition in anti-cancer immunotherapy strategies.Graphical abstractDisplay OmittedHighlights•Immunopeptidomic neoepitope discovery workflow employing public DNA sequencing data•Identification of immunogenic frameshift-derived InDel neoepitopes in an MSI model•NMD inhibition increases HLA class I-mediated presentation of InDel neoepitopes•CKAP2frameshift mutation is highly recurrent in different types of MSI cancerBiological Sciences ; Immunology ; Cancer