| Title: |
Effects of oncolytic immunotherapy with RP1 (vusolimogene oderparepvec) on immune cells mediate responsiveness to anti-PD-1 via STING-mediated interferon signaling |
| Authors: |
Roulstone, Victoria; Kyula, Joan; Appleton, Elizabeth; Bommareddy, Praveen K; Patrikeev, Anton; Jones, Sylwia; Kuncheria, Linta; Chan Wah Hak, Charleen ML; Foo, Shane; Baldock, Holly; Wongariyapak, Amarin; Leslie, Isla; Pickering, Robert; Zierhut, Christian; Smith, Henry G; Mohan, Nitya; Murano, Carmen; Hubbard, Lisa C; Dean, Isaac; Patin, Emmanuel Christian; Gkantalis, Jim; Mansfield, David; Pedersen, Malin; McLaughlin, Martin; Goicoechea, Maria; Layzell, Scott; Mannion, Jonathan; Fernando, Winnie; Meier, Pascal; Vile, Richard; Melcher, Alan; Coffin, Robert S; Harrington, Kevin J |
| Contributors: |
Cancer Research UK; Replimune Inc |
| Source: |
Journal for ImmunoTherapy of Cancer ; volume 14, issue 3, page e013692 ; ISSN 2051-1426 |
| Publisher Information: |
BMJ |
| Publication Year: |
2026 |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1136/jitc-2025-013692 |
| Availability: |
https://doi.org/10.1136/jitc-2025-013692; https://syndication.highwire.org/content/doi/10.1136/jitc-2025-013692 |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.5ECBEA45 |
| Database: |
BASE |