Looking to uncover resistance mechanisms to oncolytic virotherapy, Huff et al. found that treatment with the oncolytic vesicular stomatitis virus (VSV) resulted in IFNβ-dependent tumor upregulation of APOBEC3, a cytosine deaminase that induces mutations leading to both virus restriction and cancer progression. APOBEC3 overexpression in mouse tumor cells promoted resistance to the virus and reduced the oncolytic activity of VSV, while knockdown of APOBEC3 reduced B16 melanoma development and improved survival in mice treated with VSV. Human APOBEC3B has a similar role in human tumor cell lines.
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-beta-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.
Author Info: (1) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (2) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (3) Department of Molecula
Author Info: (1) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (2) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (3) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (4) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (5) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (6) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (7) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (8) Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. (9) Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. (10) Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA. (11) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (12) Institute of Cancer Research, London, UK. (13) Institute of Cancer Research, London, UK. (14) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (15) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK.
