APOBEC3 Mediates Resistance to Oncolytic Viral Therapy.
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Date
2018-12-21Author
Huff, AL
Wongthida, P
Kottke, T
Thompson, JM
Driscoll, CB
Schuelke, M
Shim, KG
Harris, RS
Molan, A
Pulido, JS
Selby, PJ
Harrington, KJ
Melcher, A
Evgin, L
Vile, RG
Type
Journal Article
Metadata
Show full item recordAbstract
Tumor cells frequently evade applied therapies through the accumulation of genomic mutations and rapid evolution. In the case of oncolytic virotherapy, understanding the mechanisms by which cancer cells develop resistance to infection and lysis is critical to the development of more effective viral-based platforms. Here, we identify APOBEC3 as an important factor that restricts the potency of oncolytic vesicular stomatitis virus (VSV). We show that VSV infection of B16 murine melanoma cells upregulated APOBEC3 in an IFN-β-dependent manner, which was responsible for the evolution of virus-resistant cell populations and suggested that APOBEC3 expression promoted the acquisition of a virus-resistant phenotype. Knockdown of APOBEC3 in B16 cells diminished their capacity to develop resistance to VSV infection in vitro and enhanced the therapeutic effect of VSV in vivo. Similarly, overexpression of human APOBEC3B promoted the acquisition of resistance to oncolytic VSV both in vitro and in vivo. Finally, we demonstrate that APOBEC3B expression had a direct effect on the fitness of VSV, an RNA virus that has not previously been identified as restricted by APOBEC3B. This research identifies APOBEC3 enzymes as key players to target in order to improve the efficacy of viral or broader nucleic acid-based therapeutic platforms.
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Research team
Translational Immunotherapy
Language
eng
Date accepted
2018-08-23
License start date
2018-12
Citation
Molecular therapy oncolytics, 2018, 11 pp. 1 - 13
Publisher
CELL PRESS