Oncolytic virotherapy enhances the efficacy of a cancer vaccine by modulating the tumor microenvironment

• Published in: International journal of cancer 2019-10, Vol.145 (7), p.1958-1969
• Main Authors: Koske, Iris, Rössler, Annika, Pipperger, Lisa, Petersson, Monika, Barnstorf, Isabel, Kimpel, Janine, Tripp, Christoph H., Stoitzner, Patrizia, Bánki, Zoltán, Laer, Dorothee
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cancer therapies; Cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - pharmacology; CD8 antigen; CD8 T cells; Cell Line, Tumor; Combined Modality Therapy; Cytokines; DC‐based immunotherapy; Dendritic cells; Depletion; Female; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Immune checkpoint inhibitors; Immunoregulation; Immunotherapy; Inflammation; Lymphocytes; Lymphocytes T; Lymphocytic choriomeningitis virus - genetics; Lymphocytic choriomeningitis virus - metabolism; Medical research; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Natural killer cells; Oncolysis; oncolytic virotherapy; Oncolytic Virotherapy - methods; Oncolytic Viruses - physiology; Ovalbumin; Ovalbumin - immunology; Stomatitis; Synergism; Treatment Outcome; Tumor Immunology and Microenvironment; tumor microenvironment; Tumor Microenvironment - drug effects; Tumors; Vaccines; Vesicular stomatitis Indiana virus - metabolism; Vesicular stomatitis Indiana virus - physiology; Viral Proteins - genetics; Viral Proteins - metabolism; Viruses; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32325

The efficacy of cancer vaccines has been limited by the immunosuppressive tumor microenvironment, which can be alleviated by immune checkpoint inhibitor (ICI) therapy. Here, we tested if oncolytic viruses (OVs), similar to ICI, can also synergize with cancer vaccines by modulating the tumor microenvironment. VSV‐GP, a chimeric vesicular stomatitis virus (VSV) pseudotyped with the glycoprotein (GP) of the lymphocytic choriomeningitis virus, is a promising new OV candidate. Here, we show that in mouse B16‐OVA melanoma, combination treatment of VSV‐GP with an ovalbumin (OVA) peptide‐loaded dendritic cell (DC) vaccine (DCVacc) significantly enhanced survival over the single agent therapies, although both DCVacc and DCVacc/VSV‐GP treatments induced comparable levels of OVA‐specific CD8 T cell responses. Virus replication was minimal so that direct viral oncolysis in B16‐OVA did not contribute to this synergism. The strong therapeutic effect of the DCVacc/VSV‐GP combination treatment was associated with high numbers of tumor‐infiltrating, highly activated T cells and the relative reduction of regulatory T cells in treated and contra‐lateral nontreated tumors. Accordingly, depletion of CD8 T cells but not natural killer cells abrogated the therapeutic effect of DCVacc/VSV‐GP supporting the crucial role of CD8 T cells. In addition, a drastic increase in several proinflammatory cytokines was observed in VSV‐GP‐treated tumors. Taken together, OVs, similar to ICI, have the potential to markedly increase the efficacy of cancer vaccines by alleviating local immune suppression in the tumor microenvironment. What's new? Cancer vaccine efficacy has been limited by the immunosuppressive tumor microenvironment. By inducing cancer cell death with the release of tumor‐related antigens, oncolytic viruses may have an adjuvant effect. Here, the authors show that a combination of the oncolytic rhabdovirus VSV‐GP and a dendritic cell vaccine is highly effective in the treatment of mouse melanoma, most likely because VSV‐GP reprograms the tumor microenvironment to enhance the effectivity of the vaccine‐induced immune response. Oncolytic viruses have the potential to dramatically increase the efficacy of cancer vaccines by alleviating local immune suppression in the tumor microenvironment.