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We show here that VSV-IFN\u03b2-escape tumors predictably express a point-mutated CSDE1<jats:sup>P5S<\/jats:sup> 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-IFN\u03b2 evolves a compensatory mutation in the <jats:italic>P<\/jats:italic>\/<jats:italic>M<\/jats:italic> Inter-Genic Region which rescues replication in CSDE1<jats:sup>P5S<\/jats:sup> cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1<jats:sup>P5S<\/jats:sup> 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 CSDE1<jats:sup>P5S<\/jats:sup>, 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.<\/jats:p>","DOI":"10.1038\/s41467-021-22115-1","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T11:03:37Z","timestamp":1616756617000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy"],"prefix":"10.1038","volume":"12","author":[{"given":"Timothy","family":"Kottke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Tonne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Evgin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-1798","authenticated-orcid":false,"given":"Christopher B.","family":"Driscoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3752-9499","authenticated-orcid":false,"given":"Jacob","family":"van Vloten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria A.","family":"Jennings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Huff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brady","family":"Zell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill M.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phonphimon","family":"Wongthida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Pulido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-1537","authenticated-orcid":false,"given":"Matthew R.","family":"Schuelke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel","family":"Samson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Selby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9875-0322","authenticated-orcid":false,"given":"Elizabeth","family":"Ilett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"McNiven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7885-8574","authenticated-orcid":false,"given":"Lewis R.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitesh J.","family":"Borad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardev","family":"Pandha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6014-348X","authenticated-orcid":false,"given":"Kevin","family":"Harrington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Melcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2192-9372","authenticated-orcid":false,"given":"Richard G.","family":"Vile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"22115_CR1","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1158\/2159-8290.CD-15-0344","volume":"5","author":"C Swanton","year":"2015","unstructured":"Swanton, C., McGranahan, N., Starrett, G. 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