Research ArticleCANCER IMMUNOLOGY

Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells

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Science Immunology  19 May 2017:
Vol. 2, Issue 11, eaal1713
DOI: 10.1126/sciimmunol.aal1713

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A viral STING operation for tumors

The immune response to viruses can be harnessed to attack tumors. Here, Dai et al. demonstrate that inactivated modified vaccinia virus Ankara (iMVA) can induce antitumor responses in two different models of cancer in mice. This effect relied on both Batf3-dependent dendritic cells and the cGAS-STING cytosolic DNA-sensing pathway. Moreover, intratumor injection of iMVA overcame tumor resistance to checkpoint inhibitors. Viral-induced innate immune responses may therefore tip the scale to successful cancer immunotherapy.

Abstract

Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immunosuppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. We show that infection of conventional dendritic cells (DCs) with heat- or ultraviolet-inactivated MVA leads to higher levels of interferon induction than MVA alone through the cGAS (cyclic guanosine monophosphate–adenosine monophosphate synthase)–STING cytosolic DNA-sensing pathway. Intratumoral injection of inactivated MVA (iMVA) was effective and generated adaptive antitumor immunity in murine melanoma and colon cancer models. iMVA-induced antitumor therapy was less effective in STING- or Batf3-deficient mice than in wild-type mice, indicating that both cytosolic DNA sensing and Batf3-dependent CD103+/CD8α+ DCs are essential for iMVA immunotherapy. The combination of intratumoral delivery of iMVA and systemic delivery of immune checkpoint blockade generated synergistic antitumor effects in bilateral tumor implantation models as well as in a unilateral large established tumor model. Our results suggest that inactivated vaccinia virus could be used as an immunotherapeutic agent for human cancers.

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