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Published on: April 3, 2018
Effects of oncolytic immunotherapy with RP1 (vusolimogene oderparepvec) on immune cells mediate responsiveness to
Victoria Roulstone1, Joan Kyula2, Elizabeth Appleton2
1The Institute of Cancer Research, London, UK victoria.roulstone@icr.ac.uk.
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.
Insights
Oncolytic immunotherapy (OI) combined with anti-programmed cell death protein-1 (PD-1) therapy enhances antitumor immune responses. This combination therapy, using RP1, remodels the tumor microenvironment, increasing inflammation and PD-L1 expression for improved therapeutic outcomes.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Oncolytic immunotherapy (OI) can increase programmed death-ligand 1 (PD-L1) expression, a target for cancer therapy.
- Combining OI with anti-programmed cell death protein-1 (PD-1) therapy shows promise in preclinical and clinical studies.
- Understanding the immune mechanisms underlying the interaction between oncolytic viruses and PD-1 blockade is crucial.
Purpose of the Study:
- To elucidate the immune-mediated mechanisms of interaction between oncolytic viruses and anti-PD-1 therapy.
- To investigate how oncolytic virus RP1 influences the tumor microenvironment and immune cell responses.
- To determine the role of STING and interferon signaling in the combined therapy response.
Main Methods:
- Co-culture of tumor cells and splenocytes with RP1 (oncolytic herpes simplex virus) to assess viral replication, interferon (IFN) responses, and PD-L1 expression.
- Utilized wild-type and knockout splenocytes (IFNAR1, TNFAR1, STING) to dissect immune signaling pathways.
- In vivo studies evaluated tumor immune cell infiltrates following RP1 and anti-PD-1 therapy administration.
Main Results:
- RP1 replicated in tumor cells but not splenocytes, inducing an IFN response in splenocytes via STING signaling.
- This IFN response was transmitted to tumor cells in a non-touch-dependent manner, upregulating MHC-I and PD-L1 through JAK-STAT signaling.
- In vivo, RP1 treatment increased IFN signature and PD-L1 expression in tumors, further enhanced by anti-PD-1 therapy, with recruitment of PD-L1 positive neutrophils.
Conclusions:
- RP1 effectively remodels the tumor microenvironment, inducing both direct and indirect effects on tumor and immune cells.
- The combination of RP1 and anti-PD-1 therapy promotes a more inflamed tumor phenotype.
- Data suggest a synergistic mechanism involving viral replication, immune cell activation, and PD-1 blockade for enhanced antitumor immunity.
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