CXCL12/CXCR4 Blockade by Oncolytic Virotherapy Inhibits Ovarian Cancer Growth by Decreasing Immunosuppression and Targeting Cancer-Initiating Cells

Abstract

Signals mediated by the chemokine CXCL12 and its receptor CXCR4 are involved in progression of ovarian cancer by enhancing tumor angiogenesis and immunosuppressive networks that regulate dissemination of peritoneal metastasis and development of cancer initiating cells (CICs). Here, 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 intraperitoneal delivery of a CXCR4 antagonist-expressing OVV led to reduced metastatic spread of tumors and improved overall survival over that mediated by oncolysis alone. Inhibition of tumor growth with the armed virus was associated with efficient killing of CICs, reductions in expression of ascitic CXCL12 and VEGF, and decreases in intraperitoneal numbers of endothelial and myeloid cells as well as plasmacytoid dendritic cells (pDCs). 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.

Impact of ascites volume on clinical outcomes in ovarian cancer: A cohort study

“…Luciferase-expressing MOSEC (Luc+MOSEC) cells [14] were grown in RPMI 1640 media with heat-inactivated FBS (10%), L-glutamine (2 mM), HEPES (25 mM), sodium pyruvate (1 mM), 2-mercaptoethanol (50 µM), penicillin/ streptomycin (100 µg/ml) and non-essential amino acids. Female C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME) were administered Luc+MOSEC (1.0 × 10 7 cells in 200 µl PBS) cells via intraperitoneal (IP) injection and were monitored daily by trained animal care staff.…”

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

“…CCR4 is highly expressed by Tregs in the blood and tumors (Sugiyama et al, 2013) and anti-CCR4 inhibits Treg recruitment as well as promotes antibody-dependent cell-mediated cytotoxicity (ADCC), further reducing the Treg population (Chang et al, 2012). CXCR4 is a receptor for the chemokine CXCL12 has been shown to promote an immunosuppressive tumor microenvironment through several mechanisms including Treg localization (Gil et al, 2014). …”

Harnessing the immune system to improve cancer therapy

“…Specifically, viral replication in Consequently, antigen uptake by APCs indirectly promotes a systemic T cell immune response (90,91). Genetic engineering of oncolytic viruses may further enhance their oncolytic properties and redirect them exclusively in the tumor vicinity (92).…”