Abstract
Recently, oncolytic vaccinia viruses (VACVs) have shown their potential to provide for clinically effective cancer treatments. The reason for this clinical usefulness is not only the direct destruction of infected cancer cells but also activation of immune responses directed against tumor antigens. For eliciting a robust antitumor immunity, a dominant T helper 1 (Th1) cell differentiation of the response is preferred, and such polarization can be achieved by activating the Toll-like receptor 3 (TLR3)-interferon regulatory factor 3 (IRF3) signaling pathway. However, current VACVs used as oncolytic viruses to date still encode several immune evasion proteins involved in the inhibition of this signaling pathway. By inactivating genes of selected regulatory virus proteins, we aimed for a candidate virus with increased potency to activate cellular antitumor immunity but at the same time with a fully maintained replicative capacity in cancer cells. The removal of up to three key genes (C10L, N2L, and C6L) from VACV did not reduce the strength of viral replication, both in vitro and in vivo, but resulted in the rescue of IRF3 phosphorylation upon infection of cancer cells. In syngeneic mouse tumor models, this activation translated to enhanced cytotoxic T lymphocyte (CTL) responses directed against tumor-associated antigens and neo-epitopes and improved antitumor activity.
Highlights
During the last two decades, the understanding of the relationship between cancer and the immune system has considerably changed, and implemented the role of the immune system controlling tumorigenesis and tumor progression.[1,2] Cancer immunotherapies aim to mobilize the immune system to kill cancer cells and represent a revolution in cancer therapeutics: the field has seen outstanding progress in the last decade, showing unprecedented clinical responses
The replication of oncolytic vaccinia viruses (VACVs) in cancer cells leads to the release of danger-associated molecular patterns (DAMPs) together with a multitude of tumor-specific antigens, turning “cold” tumors into “hot” tumors for more efficacious immunotherapy.[42]
We based our strategy for improving antitumor T cell responses on the observation that poly(I:C), used as an adjuvant in cancer vaccination, leads to T helper 1 (Th1) polarization,[43] which directly correlates with robust antitumor immunity in the clinic.[44]
Summary
During the last two decades, the understanding of the relationship between cancer and the immune system has considerably changed, and implemented the role of the immune system controlling tumorigenesis and tumor progression.[1,2] Cancer immunotherapies aim to mobilize the immune system to kill cancer cells and represent a revolution in cancer therapeutics: the field has seen outstanding progress in the last decade, showing unprecedented clinical responses. Challenges arise for immunotherapies when treating a larger range of cancer types, mostly due to the complexity of the immune contexture and varying tumor immunogenicity.[3,4] Antibody-mediated blockade of immune checkpoints[5,6,7] and chimeric antigen receptor (CAR) T cells[8,9,10] have spearheaded this revolution, but a large number of novel modalities are being developed showing potential in preclinical and clinical trials. VACVs are highly immunogenic, and the targeted deletion of VACV genes can further improve this immunogenicity, transforming VACVs into useful tools for activating potent antitumor immune responses.[15]
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