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Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors. | LitMetric

AI Article Synopsis

  • Modified vaccinia virus Ankara (MVA) is a genetically engineered virus used in cancer vaccines that stimulates the immune system via type I interferon (IFN) responses, though it can also lead to immunosuppression.
  • Researchers investigated the effects of statins, specifically simvastatin and atorvastatin, on IFN signaling and immune responses in cancer models, using both in vitro assays and in vivo experiments.
  • The study found that these statins act as potent inhibitors of IFN signaling by decreasing the expression of IFN receptors and enhancing dendritic cell function, which could improve the effectiveness of MVA-based cancer vaccines.

Article Abstract

Background: Modified vaccinia virus Ankara (MVA) are genetically engineered non-replicating viral vectors. Intratumoral administration of MVA induces a cyclic GMP-AMP synthase-mediated type I interferon (IFN) response and the production of high levels of the transgenes engineered into the viral genome such as tumor antigens to construct cancer vaccines. Although type I IFNs are essential for establishing CD8-mediated antitumor responses, this cytokine family may also give rise to immunosuppressive mechanisms.

Methods: In vitro assays were performed to evaluate the activity of simvastatin and atorvastatin on type I IFN signaling and on antigen presentation. Surface levels of IFN α/β receptor 1, endocytosis of bovine serum albumin-fluorescein 5 (6)-isothiocyanate, signal transducer and activator of transcription (STAT) phosphorylation, and real-time PCR of IFN-stimulated genes were assessed in the murine fibroblast cell line L929. In vivo experiments were performed to characterize the effect of simvastatin on the MVA-induced innate immune response and on the antitumor effect of MVA-based antitumor vaccines in B16 melanoma expressing ovalbumin (OVA) and Lewis lung carcinoma (LLC)-OVA tumor models. RNAseq analysis, depleting monoclonal antibodies, and flow cytometry were used to evaluate the MVA-mediated immune response.

Results: In this work, we identified commonly prescribed statins as potent IFNα pharmacological inhibitors due to their ability to reduce surface expression levels of IFN-α/β receptor 1 and to reduce clathrin-mediated endocytosis. Simvastatin and atorvastatin efficiently abrogated for 8 hours the transcriptomic response to IFNα and enhanced the number of dendritic cells presenting an OVA-derived peptide bound to major histocompatibility complex (MHC) class I. In vivo, intraperitoneal or intramuscular administration of simvastatin reduced the inflammatory response mediated by peritumoral administration of MVA and enhanced the antitumor activity of MVA encoding tumor-associated antigens. The synergistic antitumor effects critically depend on CD8 cells, whereas they were markedly improved by depletion of CD4 lymphocytes, T regulatory cells, or NK cells. Either MVA-OVA alone or combined with simvastatin augmented B cells, CD4 lymphocytes, CD8 lymphocytes, and tumor-specific CD8 in the tumor-draining lymph nodes. However, only the treatment combination increased the numbers of these lymphocyte populations in the tumor microenvironment and in the spleen.

Conclusion: In conclusion, blockade of IFNα functions by simvastatin markedly enhances lymphocyte infiltration and the antitumor activity of MVA, prompting a feasible drug repurposing.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320251PMC
http://dx.doi.org/10.1136/jitc-2020-001587DOI Listing

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