%0 Journal Article
%T Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response.
%A Webb MJ
%A Sangsuwannukul T
%A van Vloten J
%A Evgin L
%A Kendall B
%A Tonne J
%A Thompson J
%A Metko M
%A Moore M
%A Chiriboga Yerovi MP
%A Olin M
%A Borgatti A
%A McNiven M
%A Monga SPS
%A Borad MJ
%A Melcher A
%A Roberts LR
%A Vile R
%J Nat Commun
%V 15
%N 1
%D 2024 Jun 27
%M 38937436
%F 17.694
%R 10.1038/s41467-024-49286-x
%X 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.