{
  "abstract": "Background Antitumor immune responses induced by oncolytic immunotherapy (OI) are often followed by upregulation of programmed death-ligand 1 (PD-L1). As such, the combination of OI with blockade of the programmed cell death protein-1 (PD-1)/PD-L1 axis has demonstrated therapeutic activity in preclinical and clinical trials. The purpose of this study is to understand further the immune-mediated mechanism of interaction between oncolytic viruses and anti-PD-1 therapy.Methods Tumor cells and immune cells (splenocytes) were cultured separately, or in co-culture with vusolimogene oderparepvec, an oncolytic herpes simplex virus expressing the fusogenic gibbon-ape leukemia virus-fusogenic membrane glycoprotein protein (GALV) and granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as RP1. Viral replication, interferon (IFN) responses and PD-L1 expression were analyzed using wild-type, IFNAR1, TNFAR1 and STING knockout splenocytes. In vivo studies evaluated immune cell infiltrates into the tumor following RP1 administration with anti-PD-1 therapy.Results RP1 replication was evident in tumor cells but not splenocytes. This was also accompanied by upregulated IFN expression in cultured splenocytes that was absent in cultured tumor cells. However, when these cell types were co-cultured, splenocytes mediated an interferon response to RP1 via STING that was transmitted to tumor cells in a non-touch-dependent manner. Tumor cells responded to these input signals via upregulation of cell surface major histocompatibility complex-I and PD-L1 through tumor intrinsic JAK-STAT signaling. In vivo, an IFN signature was observed following intratumoral injection of RP1, both in injected and non-injected tumors, which was further increased when combined with anti-PD-1 therapy. Marked upregulation of PD-L1 was observed in tumors injected with RP1 accompanied by the recruitment of CD11b+Ly6G+neutrophils into the tumor microenvironment, which stained positive for PD-L1.Conclusion Overall, the data demonstrate that RP1 remodels the tumor microenvironment through a combination of direct and indirect effects on both tumor and immune cells, resulting in an overall more inflamed phenotype.",
  "authors": [
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Victoria Roulstone"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Joan Kyula"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Elizabeth Appleton"
    },
    {
      "affiliations": [
        "Replimune Inc, Woburn, Massachusetts, USA"
      ],
      "name": "Praveen K Bommareddy"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Anton Patrikeev"
    },
    {
      "affiliations": [
        "Replimune Inc, Woburn, Massachusetts, USA"
      ],
      "name": "Sylwia Jones"
    },
    {
      "affiliations": [
        "Replimune Inc, Woburn, Massachusetts, USA"
      ],
      "name": "Linta Kuncheria"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Charleen ML Chan Wah Hak"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Shane Foo"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Holly Baldock"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Amarin Wongariyapak"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Isla Leslie"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Robert Pickering"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Christian Zierhut"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Henry G Smith"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Nitya Mohan"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Carmen Murano"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Lisa C Hubbard"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Isaac Dean"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Emmanuel Christian Patin"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Jim Gkantalis"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "David Mansfield"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Malin Pedersen"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Martin McLaughlin"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Maria Goicoechea"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Scott Layzell"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Jonathan Mannion"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Winnie Fernando"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Pascal Meier"
    },
    {
      "affiliations": [
        "Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"
      ],
      "name": "Richard Vile"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Alan Melcher"
    },
    {
      "affiliations": [
        "Replimune Inc, Woburn, Massachusetts, USA"
      ],
      "name": "Robert S Coffin"
    },
    {
      "affiliations": [
        "The Institute of Cancer Research, London, UK"
      ],
      "name": "Kevin J Harrington"
    }
  ],
  "title": "Effects of oncolytic immunotherapy with RP1 (vusolimogene oderparepvec) on immune cells mediate responsiveness to anti-PD-1 via STING-mediated interferon signaling",
  "uid": "0452e707-9064-5976-84b1-29bd78b25f3c"
}