Recruitment of Intratumoral CD103+ Dendritic Cells by a CXCR4 Antagonist-Armed Virotherapy Enhances Antitumor Immunity

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...

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Bibliographic Details
Published in:Molecular therapy. Oncolytics 2019-09, Vol.14, p.233-245
Main Authors: Mistarz, Anna, Komorowski, Marcin P., Graczyk, Matthew A., Gil, Margaret, Jiang, Aimin, Opyrchal, Mateusz, Rokita, Hanna, Odunsi, Kunle O., Kozbor, Danuta
Format: Article
Language:English
Subjects:
Adaptive immunity
Antigen (tumor-associated)
Antigens
Antitumor activity
Cancer therapies
cancer vaccine
Cancer vaccines
CD103 antigen
Clinical trials
CXCR4 antagonist
CXCR4 protein
Cytokines
Cytotoxicity
Data analysis
Dendritic cells
Experiments
Flow cytometry
Growth factors
Immunization
Immunotherapy
Laboratory animals
Lymphocytes
Lymphocytes T
Metastases
Metastasis
Oncolysis
Ovarian cancer
Peptides
Phagocytes
Protein-tyrosine kinase
Recruitment
T cells
Tumors
Vaccines
virotherapy
Viruses
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Summary: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.
ISSN:2372-7705
2372-7705
DOI:10.1016/j.omto.2019.06.003