Abstract
Intratumoral dendritic cells play an important role in stimulating cytotoxic T cells and driving antitumor immunity. Using a metastatic ovarian tumor model in syngeneic mice, we explored whether therapy with a CXCR4 antagonist-armed oncolytic vaccinia virus activates endogenous CD103+ dendritic cell responses associated with the induction of adaptive immunity against viral and tumor antigens. The overall goal of this study was to determine whether expansion of CD103+ dendritic cells by the virally delivered CXCR4 antagonist augments overall survival and in situ boosting with a tumor antigen peptide-based vaccine. We found that locoregional delivery of the CXCR4-A-armed virus reduced the tumor load and the immunosuppressive network in the tumor microenvironment, leading to infiltration of CD103+ dendritic cells that were capable of phagocytic clearance of cellular material from virally infected cancer cells. Further expansion of tumor-resident CD103+ DCs by injecting the FMS-related tyrosine kinase 3 ligand, the formative cytokine for CD103+ DCs, provided a platform for a booster immunization with the Wilms tumor antigen 1 peptide-based vaccine delivered intraperitoneally with polyriboinosinic:polyribocytidylic acid as an adjuvant. The vaccine-induced antitumor responses inhibited tumor growth and increased overall survival, indicating that expansion of intratumoral CD103+ dendritic cells by CXCR4-A-armed oncovirotherapy treatment can potentiate in situ cancer vaccine boosting.
Highlights
To be effective, cancer vaccine strategies need to promote the release of tumor antigens in the context of immunogenic tumor cell death (ICD), limit multiple levels of immunosuppression in the tumor microenvironment (TME), and increase intratumoral dendritic cell (DC) populations capable of stimulating cytotoxic T cells and driving immune responses against cancer.[1,2] Alongside traditional ICD inducers like selected chemotherapies and radiation, oncolytic viruses (OVs) have emerged as new members of this class of agents.[4]
We have recently demonstrated that the innate resistance properties of highly metastatic ovarian tumors, together with the tumor immunosuppressive network, could be overcome by the oncolytic vaccinia virus (OVV)-delivered CXCR4 antagonist (CXCR4-A), which was effective in combination with doxorubicin-mediated killing.[8]
As cancer therapies continue to evolve and incorporate immunotherapy as an integral aspect of treatment, developing approaches that potentiate the induction of ICD and overcome non-T cell inflamed tumors will be important to realizing increased treatment efficacy
Summary
Cancer vaccine strategies need to promote the release of tumor antigens in the context of immunogenic tumor cell death (ICD), limit multiple levels of immunosuppression in the tumor microenvironment (TME), and increase intratumoral dendritic cell (DC) populations capable of stimulating cytotoxic T cells and driving immune responses against cancer.[1,2] Alongside traditional ICD inducers like selected chemotherapies and radiation (reviewed in Galluzzi et al.3), oncolytic viruses (OVs) have emerged as new members of this class of agents.[4]. Modulation of the CXCL12/CXCR4 axis in ovarian cancer could affect multiple aspects of tumor pathogenesis, including immune dysregulation
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