CXCL12/CXCR4 Blockade Induces Multimodal Antitumor Effects That Prolong Survival in an Immunocompetent Mouse Model of Ovarian Cancer

Abstract

The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers including ovarian cancer, where they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to demonstrate that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3+ regulatory T-cells (T-regs). Compared to controls, CXCR4 blockade greatly increased T cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral T regulatory cells was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease.

The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation

“…Interestingly, previous studies implicated the importance of other chemokine ligand-receptor interactions, such as CXCL12-CXCR4, CX 3 CL1-CX 3 CR1, and CXCL16-CXCR6, in progression and metastasis of ovarian carcinoma (8,34,(42)(43)(44). Current study on the role of XCL1-XCR1 emphasizes the complexity and importance of the chemokine ligand-receptor interactions in the peritoneal milieu of ovarian carcinoma.…”

Chemokines in tumor development and progression

“…Accumulating evidence also implicates CXCR4 in the proliferation of various cancer cells including ovarian, glioma, melanoma, lung, renal, and thyroid cancer cells [23,24]. The CXCL12/CXCR4 axis delivers surviving signals to hepatoma, ovarian, and chronic leukemia cells and CXCR4 blockade induces the apoptosis of these malignant cells [16,25,26] (Figure 1). CXCL12 expression correlates well with lower apoptosis in human myelodysplastic syndrome [27].…”

The emerging role of CXC chemokines in epithelial ovarian cancer

“…Furthermore, a significant correlation has been shown between CXCR4 expression in both primary and metastatic ovarian tumours, as well as lymph node metastases (Jiang et al 2006). In a mouse model of ovarian cancer, siRNA-mediated silencing of CXCL12 reduced tumour growth in vivo, and a CXCR4 antagonist (AMD3100) could increase T-cell-mediated anti-tumour responses (Righi et al 2011). Human primary ovarian tumour cells also express CXCL12 and VEGF following exposure to the hypoxic tumour microenvironment (Kryczek et al 2005).…”

“…In two separate studies involving mouse models of EOC, AMD3100 (a clinically approved CXCR4 inhibitor) significantly reduced ovarian cancer cell growth (Ray et al 2011, Righi et al 2011. In mice, administration of AMD3100 significantly reduced intraperitoneal dissemination and angiogenesis (measured by vessel density with the tumour), increased T-cell-mediated anti-tumour immune responses and apoptosis and reduced FoxP3 C T reg cell numbers within the tumour (Righi et al 2011). Subsequently, it was shown that AMD3100 blocked CXCL12/CXCR4 binding, resulting in prolonged survival and reduced tumour growth in mice with disseminated ovarian cancer (Ray et al 2011).…”