Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response

Mason J. Webb, Thanich Sangsuwannukul, Jacob Vloten, Laura Evgin, Benjamin Kendall, Jason Tonne, Jill Thompson, Muriel Metko, Madelyn Moore, Maria P. Chiriboga Yerovi, Michael Olin, Antonella Borgatti, Mark McNiven, Satdarshan P. S. Monga, Mitesh J. Borad, Alan Melcher, Lewis R. Roberts and Richard Vile ()
Additional contact information
Mason J. Webb: Mayo Clinic
Thanich Sangsuwannukul: Mayo Clinic
Jacob Vloten: Mayo Clinic
Laura Evgin: Mayo Clinic
Benjamin Kendall: Mayo Clinic
Jason Tonne: Mayo Clinic
Jill Thompson: Mayo Clinic
Muriel Metko: Mayo Clinic
Madelyn Moore: Mayo Clinic
Maria P. Chiriboga Yerovi: Mayo Clinic
Michael Olin: University of Minnesota
Antonella Borgatti: University of Minnesota
Mark McNiven: Mayo Clinic
Satdarshan P. S. Monga: University of Pittsburgh and UPMC
Mitesh J. Borad: Mayo Clinic
Alan Melcher: Chester Beatty Laboratories
Lewis R. Roberts: Mayo Clinic
Richard Vile: Mayo Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Date: 2024
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DOI: 10.1038/s41467-024-49286-x

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