Abstract
Immunotherapies 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alternative Splicing / genetics
-
Alternative Splicing / immunology
-
Breast Neoplasms / genetics
-
Breast Neoplasms / immunology
-
Carcinoma, Small Cell / genetics
-
Carcinoma, Small Cell / immunology
-
Cell Line, Tumor
-
Computational Biology
-
Epitopes / genetics*
-
Epitopes / immunology*
-
Female
-
Histocompatibility Antigens Class I / genetics
-
Histocompatibility Antigens Class I / immunology
-
Humans
-
Immunotherapy
-
Lung Neoplasms / genetics
-
Lung Neoplasms / immunology
-
Male
-
Melanoma / genetics
-
Melanoma / immunology
-
Models, Genetic
-
Models, Immunological
-
Mutation
-
Neoplasms / genetics*
-
Neoplasms / immunology*
-
Neoplasms / therapy
-
Protein Isoforms / genetics
-
Protein Isoforms / immunology
-
RNA Splicing / genetics
-
RNA Splicing / immunology
-
RNA-Seq
Substances
-
Epitopes
-
Histocompatibility Antigens Class I
-
Protein Isoforms
Grants and funding
This work was supported by the Agencia Estatal de Investigación (AEI), Spanish Government and European Regional Development Fund (FEDER) with grant BIO2017-85364-R (F.S., E.E.), by the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya) with grants SGR2017-1020 (E.E) and 2017 SGR 00519 (F.S), by the Instituto de Salud Carlos III (ISCIII and FEDER) with grants FI18/00034 (J.P-G) and PT17/0009/0014 (F.S), and by the AEI with CEX2018-000782-M (F.S). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB) supported by ISCIII and FEDER (PT17/0009/0014). The DCEXS is a ‘Unidad de Excelencia María de Maeztu’ supported by the AEI (CEX2018-000782-M). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.