Using a slow-developing multifocal tumor model of HCC (SB-HCC) that was partially responsive to PD-L1, Webb et al. tested the addition of an oncolytic vesicular stomatitis virus expressing interferon-β (VSV-IFNβ), and found that it antagonized the effects of anti-PD-L1 due to the overexpansion of one or a few dominant virus-specific T cell populations at the expense of subdominant tumor-specific populations that were otherwise expanded following anti-PD-L1. However, encoding a range of HCC tumor antigens (cDNA library derived from three different SB-HCC explants) within VSV restored and improved upon the therapeutic benefit.
Contributed by Lauren Hitchings
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-§ (VSV-IFN§), 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-IFN§ 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.
Author Info: (1) Department of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. (2) Department of M
Author Info: (1) Department of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA. 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. Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z1L3, Canada. Michael Smith Genome Sciences Department, BC Cancer Research Institute, Vancouver, BC, V5Z1L3, Canada. (5) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. (6) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. (7) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. (8) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. (9) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA. (10) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. (11) Division of Pediatric Hematology and Oncology, University of Minnesota, Minneapolis, MN, 55455, USA. (12) Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN, 55108, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. Clinical Investigation Center, University of Minnesota, St. Paul, MN, 55108, USA. (13) Mayo Center for Biomedical Discovery, Mayo Clinic, Rochester, MN, 55905, USA. (14) Pittsburgh Liver Institute, University of Pittsburgh and UPMC, Pittsburgh, PA, 15261, USA. (15) Department of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ, 85054, USA. (16) Division of Radiotherapy and Imaging, Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK. (17) Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA. (18) Department of Molecular Medicine, Mayo Clinic, Rochester, MN, 55905, USA. vile.richard@mayo.edu. Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA. vile.richard@mayo.edu. Joan Reece Department of Immuno-oncology, King's College London, London, UK. vile.richard@mayo.edu.
