CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells

Signals mediated by the chemokine CXCL12 and its receptor CXCR4 are involved in the progression of ovarian cancer through enhancement of tumor angiogenesis and immunosuppressive networks that regulate dissemination of peritoneal metastasis and development of cancer-initiating cells (CICs). In this s...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2014-11, Vol.193 (10), p.5327-5337
Main Authors: Gil, Margaret, Komorowski, Marcin P, Seshadri, Mukund, Rokita, Hanna, McGray, A J Robert, Opyrchal, Mateusz, Odunsi, Kunle O, Kozbor, Danuta
Format: Article
Language:English
Subjects:
Animals
Carcinoma in Situ - genetics
Carcinoma in Situ - immunology
Carcinoma in Situ - pathology
Carcinoma in Situ - therapy
Cell Proliferation
Chemokine CXCL12 - antagonists & inhibitors
Chemokine CXCL12 - genetics
Chemokine CXCL12 - immunology
Dendritic Cells - immunology
Dendritic Cells - pathology
Endothelial Cells - immunology
Endothelial Cells - pathology
Female
Gene Expression
Humans
Mice
Mice, Inbred C57BL
Mice, SCID
Neoplasm Transplantation
Neoplastic Stem Cells - immunology
Neoplastic Stem Cells - pathology
Oncolytic Virotherapy - methods
Ovarian Neoplasms - genetics
Ovarian Neoplasms - immunology
Ovarian Neoplasms - pathology
Ovarian Neoplasms - therapy
Peritoneal Neoplasms - genetics
Peritoneal Neoplasms - immunology
Peritoneal Neoplasms - prevention & control
Peritoneal Neoplasms - secondary
Receptors, CXCR4 - antagonists & inhibitors
Receptors, CXCR4 - genetics
Receptors, CXCR4 - immunology
Signal Transduction
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - pathology
Tumor Burden
Vaccinia virus
Vaccinia virus - immunology
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Summary:Signals mediated by the chemokine CXCL12 and its receptor CXCR4 are involved in the progression of ovarian cancer through enhancement of tumor angiogenesis and immunosuppressive networks that regulate dissemination of peritoneal metastasis and development of cancer-initiating cells (CICs). In this study, we investigated the antitumor efficacy of a CXCR4 antagonist expressed by oncolytic vaccinia virus (OVV) against an invasive variant of the murine epithelial ovarian cancer cell line ID8-T. This variant harbors a high frequency of CICs that form multilayered spheroid cells and express the hyaluronan receptor CD44, as well as stem cell factor receptor CD117 (c-kit). Using an orthotopic ID8-T tumor model, we observed that i.p. delivery of a CXCR4 antagonist-expressing OVV led to reduced metastatic spread of tumors and improved overall survival compared with oncolysis alone. Inhibition of tumor growth with the armed virus was associated with efficient killing of CICs, reduced expression of ascitic CXCL12 and vascular endothelial growth factor, and decreases in i.p. numbers of endothelial and myeloid cells, as well as plasmacytoid dendritic cells. These changes, together with reduced recruitment of T regulatory cells, were associated with higher ratios of IFN-γ(+)/IL-10(+) tumor-infiltrating T lymphocytes, as well as induction of spontaneous humoral and cellular antitumor responses. Similarly, the CXCR4 antagonist released from virally infected human CAOV2 ovarian carcinoma cells inhibited peritoneal dissemination of tumors in SCID mice, leading to improved tumor-free survival in a xenograft model. Our findings demonstrate that OVV armed with a CXCR4 antagonist represents a potent therapy for ovarian CICs with a broad antitumor repertoire.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1400201