Type I interferon (IFN), well known for its antiviral activity, is a critical component of cancer immune surveillance through its direct actions on cancer cells as well as on tumor microenvironment. Advanced melanoma remains a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immune suppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses are cytosolic DNA viruses that have been investigated as oncolytic and immunotherapeutic agents. We recently reported that the highly attenuated modified vaccinia virus Ankara (MVA), a safe vaccine for smallpox, triggers type I IFN production in conventional dendritic cells (cDCs) via the cytosolic DNA sensor cGAS and its adaptor STING, and that it requires transcription factors IRF3 and IRF7. Here we show that infection of cDCs with heat-inactivated MVA leads to higher levels of IFN induction than MVA. This induction is also mediated by the cytosolic DNA-sensing pathway cGAS/STING/IRF3/IRF7. In addition, we found that intratumoral injection of Heat-MVA caused tumor eradication in a murine B16 melanoma model as well as the generation of adaptive anti-tumor immunity. Furthermore, Heat-MVA-induced anti-tumor therapy is less effective in STING, IRF7, or Batf3-deficient mice than in wild-type mice, indicating that both the innate immune-sensing pathway and CD8α+DCs are essential for Heat-MVA-based immunotherapy. Lastly, the combination of intratumoral delivery of Heat-MVA with systemic delivery of anti-CTLA-4, PD-1 or PD-L1 antibodies achieved enhanced efficacy in tumor eradication and survival than Heat-MVA alone. Our results have strong implications for the development of poxvirus-based cancer immunotherapeutics as well novel strategies to overcome resistance to immune checkpoint blockade therapy.
Citation Format: Peihong Dai, Weiyi Wang, Cristian Serna-Tamayo, Dimitriy Zamarin, Stewart Shuman, Taha Merghoub, Jedd D. Wolchok, Liang Deng. Heat-inactivated modified vaccinia virus ankara induces type I IFN and antitumor immunity via the cytosolic DNA-sensing pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B031.
- ©2016 American Association for Cancer Research.