CXCL12/CXCR4 blockade induces multimodal anti-tumor effects thatprolong survival in an immunocompetent mouse model of ovariancancer

摘要

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 confirmedin a melanoma model. Together, our findings reinforce the concept of a criticalrole for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer adefinitive preclinical validation of CXCR4 as a therapeutic target in thisdisease.