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Journal article
Large-Scale Immuno-Peptidome Analysis Reveals Recurrent Post-Translational Splicing of Cancer and Immune-Associated Genes
Molecular & cellular proteomics, Vol.22(4), 100519
Apr/2023
PMID: 36828127
Abstract
Post-translational spliced peptides (PTSPs) are a unique class of peptides that have been found to be presented by HLA-class-I molecules in cancer (1). Thus far, no consensus has been reached on the proportion of PTSPs in the immunopeptidome, with estimates ranging from 2% to as high as 45% and stirring significant debate (2-8). Furthermore, the role of the HLA-class-II pathway in PTSP presentation has been studied only in diabetes (9). Here, we exploit our large-scale cancer peptidomics database and our newly devised pipeline for filtering spliced peptide predictions to identify recurring spliced peptides, both for HLA-class-I and -II complexes. Our results indicate that HLA-class-I spliced peptides account for a low percentage of the immunopeptidome (less than 3.1%), yet are larger in number relative to other types of identified aberrant peptides. Therefore, spliced peptides significantly contribute to the repertoire of presented peptides in cancer cells. In addition, we identified HLA-class-II-bound spliced peptides, but to a lower extent (less than 0.5%). The identified spliced peptides include cancer- and immune-associated genes, such as the MITF oncogene, DAPK1 tumor suppressor and HLA-E, which were validated using synthetic peptides. The potential immunogenicity of the DAPK1- and HLA-E-derived PTSPs was also confirmed. In addition, a reanalysis of our published mouse single-cell clone immunopeptidome dataset showed that most of the spliced peptides were found repeatedly in a large number of the single-cell clones. Establishing a novel search-scheme for the discovery and evaluation of recurring PTSPs among cancer patients may assist in identifying potential novel targets for immunotherapy.
Details
- Title
- Large-Scale Immuno-Peptidome Analysis Reveals Recurrent Post-Translational Splicing of Cancer and Immune-Associated Genes
- Creators
- Ronen Levy - 972WIS_INST___122Tal Alter Regev - 972WIS_INST___122Wayne Paes - University of OxfordNofar Gumpert - 972WIS_INST___122Sapir Cohen Shvefel - 972WIS_INST___122Osnat Bartok - 972WIS_INST___122Maria Dayan-Rubinov - 972WIS_INST___122Michal Alon - 972WIS_INST___122MeravD Shmueli - 972WIS_INST___121Yishai Levin - 972WIS_INST___122Yifat Merbl - 972WIS_INST___121Nicola Ternette - University of OxfordYardena Samuels (Corresponding Author) - 972WIS_INST___122
- Resource Type
- Journal article
- Publication Details
- Molecular & cellular proteomics, Vol.22(4), 100519; Apr/2023
- Number of pages
- 14
- Publisher
- Elsevier Inc
- Language
- English
- DOI
- https://doi.org/10.1016/j.mcpro.2023.100519
- PMID
- 36828127
- Grant note
- We would like to thank Moshe Elkabets from Ben-Gurion University, Israel, for sharing the tissue of SCC47. Y.S. is supported by the Israel Science Foundation (grant no. 696/17), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 770854), MRA (no. 917324), Minerva, Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, Estate of Alice Schwarz-Gardos, Estate of John Hunter, Knell Family, and Peter and Patricia Gruber Award. Author contributions: R.L. conceived the project and analyzed computationally all types of bioinformatics data in the manuscript; Y.S. supervised the project; R.L., T.A.R. and Y.S. participated in writing the paper; T.A.R. performed and analyzed the TIL experiments; T.A.R. and N.G. performed and analyzed the PBMC immunogenicity experiments; S.C.S. and M.D.R provided experimental support; O.B. prepared RNA libraries included in the manuscript; W.P., N.T., M.D.S. and Y.M. participated in masspectrometry validations; Y.L. performed mass spectrometry for immunopeptidomics samples; M.A., and Y.L. performed isotopically-labelled peptide validation;
- Record Identifier
- 993432540903596
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