Trincado Alonso, Juan Luis, 1987-Reixachs i Solé, MarinaPérez-Granado, JudithFugmann, TimSanz, FerranYokota, JunEyras Jiménez, Eduardo2022-03-182022-03-182021Trincado JL, Reixachs-Solé M, Pérez-Granado J, Fugmann T, Sanz F, Yokota J et al. ISOTOPE: ISOform-guided prediction of epiTOPEs in cancer. PLoS Comput Biol. 2021 Sep 16;17(9):e1009411. DOI: 10.1371/journal.pcbi.10094111553-734Xhttp://hdl.handle.net/10230/52718Immunotherapies provide effective treatments for previously untreatable tumors and identifying tumor-specific epitopes can help elucidate the molecular determinants of therapy response. Here, we describe a pipeline, ISOTOPE (ISOform-guided prediction of epiTOPEs In Cancer), for the comprehensive identification of tumor-specific splicing-derived epitopes. Using RNA sequencing and mass spectrometry for MHC-I associated proteins, ISOTOPE identified neoepitopes from tumor-specific splicing events that are potentially presented by MHC-I complexes. Analysis of multiple samples indicates that splicing alterations may affect the production of self-epitopes and generate more candidate neoepitopes than somatic mutations. Although there was no difference in the number of splicing-derived neoepitopes between responders and non-responders to immune therapy, higher MHC-I binding affinity was associated with a positive response. Our analyses highlight the diversity of the immunogenic impacts of tumor-specific splicing alterations and the importance of studying splicing alterations to fully characterize tumors in the context of immunotherapies. ISOTOPE is available at https://github.com/comprna/ISOTOPE.application/pdfeng© 2021 Trincado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedCàncerImmunoteràpiaIdentificacióinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1371/journal.pcbi.1009411info:eu-repo/semantics/openAccess