We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy.
- Authors
Kottke, Timothy; Tonne, Jason; Evgin, Laura; Driscoll, Christopher B.; van Vloten, Jacob; Jennings, Victoria A.; Huff, Amanda L.; Zell, Brady; Thompson, Jill M.; Wongthida, Phonphimon; Pulido, Jose; Schuelke, Matthew R.; Samson, Adel; Selby, Peter; Ilett, Elizabeth; McNiven, Mark; Roberts, Lewis R.; Borad, Mitesh J.; Pandha, Hardev; Harrington, Kevin
- 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. Oncolytic viruses, such as vesicular stomatitis virus (VSV), are a promising class of cancer therapeutics. Here the authors report that a mutation in the CSDE1 gene renders cancer cells resistant to VSV replication and oncolysis, but a mutation-derived escape-associated neoantigen could be exploited for immunotherapy against treatment-resistant tumors.
- Subjects
ONCOLYTIC virotherapy; VESICULAR stomatitis; IMMUNOTHERAPY; ALEMTUZUMAB; T cells; PHENOTYPES; CYTOTOXIC T cells
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22115-1