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. 2024 Apr 10;25(5):2220–2238. doi: 10.1038/s44319-024-00128-3

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.

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(A) Venn diagram shows an overlap between alternatively spliced mRNAs in SW-480 and HT-29 colon adenocarcinomas and previously reported neoantigen-producing mRNAs (Lu et al, 2021). (B) In silico prediction of MHC-I binders derived from alternative splicing events triggered by LB-100 in SW-480 and HT-29 human colorectal adenocarcinomas. (C) Alternative splicing event within HNRNPM gene and representative Sashimi plots showing differential splicing in untreated and LB-100-treated SW-480 cells. Intron 6-derived peptides predicted to bind MHC-I are underlined. (D) Experimental setup employed to capture immunopeptides presented in MHC-I context in response to PP2A/PP5 inhibitor LB-100 in human colorectal adenocarcinoma (hCoAD) cell line HT-29. (E) Sequence logo for 9-mers identified from the MHC-I immunopurification in untreated controls (Untr.) and LB-100-treated HT-29 colorectal adenocarcinoma cell line. (F) The volcano plot shows changes in the MHC-I presentation of individual peptides in response to LB-100 stimulation compared to untreated controls. Heat map shows levels of detection for 141 significant (p value <0.05, t-test) peptides detected only in LB-100-treated cells compared to untreated controls (Untr.) in n = 3 biological replicates. (G) The graph depicts the type of detected alternative splicing events in seven transcripts being a source for peptides detected only in LB-100-treated cells. (H) Working model. LB-100-mediated phosphorylation changes in spliceosome drive differential splicing patterns in human colorectal carcinoma. Predominant exon skipping and intron retention events affect DNA damage responses and neoantigen formation, with possible implications for therapy response. Data information: In (A), statistical significance was calculated with a hypergeometric test, ****p < 0.0001. See also Fig. EV5 and Datasets EV5, EV6.