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Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy
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DOI：10.1038/s41467-021-22115-1.png)
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Abstract
En 中文
In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFN beta), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFN beta -escape tumors predictably express a point-mutated CSDE1(P5S) 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 beta evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1(P5S) cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1(P5S) 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(P5S), 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.
Keywords:
VESICULAR STOMATITIS-VIRUS
HUMAN DENDRITIC CELLS
IL-12 PRODUCTION
CANCER
MELANOMA
DEFECTS
UNR
IDENTIFICATION
TRANSLATION
NEOANTIGENS
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