Kottke, Timothy, Tonne, Jason, Evgin, Laura et al. (19 more authors) (2021) Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy. Nature Communications. 1930. ISSN: 2041-1723
Abstract
In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © The Author(s) 2021 |
Keywords: | Animals,Cancer Vaccines/administration & dosage,Cell Line, Tumor,DNA-Binding Proteins/genetics,Female,Humans,Immunotherapy/methods,Interferon-beta/immunology,Mice, Inbred C57BL,Mutation,Oncolytic Virotherapy/methods,Oncolytic Viruses/immunology,RNA-Binding Proteins/genetics,T-Lymphocytes/immunology,Vesicular stomatitis Indiana virus/immunology,Virus Replication/immunology,Mice |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Biology (York) > Jack Birch Unit for Molecular Carcinogenesis (York) |
Depositing User: | Pure (York) |
Date Deposited: | 28 Aug 2025 15:50 |
Last Modified: | 28 Aug 2025 23:09 |
Published Version: | https://doi.org/10.1038/s41467-021-22115-1 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-021-22115-1 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:230919 |