Dai et al. injected heat-inactivated modified vaccinia virus Ankara (iMVA) into melanoma and colon cancer tumors in mice and observed maturation of dendritic cells via cGAS-STING and Batf4-dependent pathways, type-I interferon production, and CD8+ T cell responses that eradicated injected tumors and controlled distant non-injected tumors, particularly in combination with checkpoint blockade.
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+/CD8alpha+ 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.
Author Info: (1) Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Molecular Biology Program, Memorial Sloan Kettering Cancer Center,
Author Info: (1) Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical and Graduate Colleges, New York, NY 10065, USA. (7) Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (8) Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (9) Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical and Graduate Colleges, New York, NY 10065, USA. (10) Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. dengl@mskcc.org. Weill Cornell Medical and Graduate Colleges, New York, NY 10065, USA.
