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

• Published in: Nature communications Vol. 15; no. 1; pp. 5442 - 18
• Main Authors: Webb, Mason J., Sangsuwannukul, Thanich, van Vloten, Jacob, Evgin, Laura, Kendall, Benjamin, Tonne, Jason, Thompson, Jill, Metko, Muriel, Moore, Madelyn, Chiriboga Yerovi, Maria P., Olin, Michael, Borgatti, Antonella, McNiven, Mark, Monga, Satdarshan P. S., Borad, Mitesh J., Melcher, Alan, Roberts, Lewis R., Vile, Richard
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/21; 13/31; 13/51; 42/40; 631/250/2152/1566/1618; 631/250/2520; 631/67/1059/2325; 631/67/1504/1610/4029; 64/60; Animals; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Antiviral agents; Antiviral drugs; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - therapy; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Line, Tumor; Cytometry; Disease resistance; Effector cells; Female; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunogenicity; Inflammation; Interferon-beta - immunology; Interferon-beta - metabolism; Liver cancer; Liver Neoplasms - immunology; Liver Neoplasms - therapy; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Microenvironments; multidisciplinary; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Oncolytic Viruses - immunology; PD-L1 protein; Populations; Science; Science (multidisciplinary); Stomatitis; T-Lymphocytes - immunology; Therapy; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Vesiculovirus - genetics; Vesiculovirus - immunology; Viruses; β-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49286-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. Oncolytic viruses create an inflamed tumour microenvironment allowing T cells to respond to immune checkpoint blockade therapy more efficiently. Authors here show that in a hepatocellular carcinoma model, a dominant anti-viral rather than anti-tumour T cell response is elicited by an oncolytic vesicular stomatitis virus, unless the virus is designed to express tumour antigens, which restores therapeutic benefit.