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Type-1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus

Aref, S; Castleton, AZ; Bailey, K; Burt, R; Dey, A; Leongamornlert, D; Mitchell, RJ; ... Fielding, AK; + view all (2020) Type-1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus. Molecular Therapy , 28 (4) pp. 1043-1055. 10.1016/j.ymthe.2020.01.027. Green open access

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Abstract

The mechanism of tumor selective replication of oncolytic measles virus (MV) is poorly understood. Using a step-wise model of cellular transformation, in which oncogenic hits were additively expressed in human bone marrow-derived mesenchymal stromal cells, we show that MV-induced oncolysis increased progressively with transformation. Type-1 interferon response to MV infection was significantly reduced and delayed, in accordance with the level of transformation. Consistently, we observed delayed and reduced STAT1 phosphorylation in the fully transformed cells. Pre-treatment with IFNβ restored resistance to MV-mediated oncolysis. Gene expression profiling to identify the genetic correlates of susceptibility to MV oncolysis revealed a dampened basal level of immune-related genes in the fully transformed cells compared to their normal counterparts. Interferon-induced transmembrane protein 1 (IFITM1) was the foremost basally downregulated immune gene. Stable IFITM1 overexpression in MV-susceptible cells resulted in a 50% increase in cell viability and a significant reduction in viral replication at 24 hours post MV infection. Overall, our data indicate that the basal reduction in functions of the type 1 IFN pathway is a major contributor to the oncolytic selectivity of MV. In particular, we have identified IFITM1 as a restriction factor for oncolytic MV, acting at early stages of infection.

Type: Article
Title: Type-1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ymthe.2020.01.027
Publisher version: https://doi.org/10.1016/j.ymthe.2020.01.027
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Innate immune response, type 1 interferon, Measles virus (MV), interferon-induced transmembrane protein 1 (IFITM1), interferon stimulated gene (ISG)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10091494
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