Blocking ovarian cancer progression by targeting tumor microenvironmental leukocytes

Abstract

Current therapies for metastatic ovarian carcinoma are based on surgical debulking followed by chemotherapy. After more than three decades implementing treatments that selectively target the tumor cell, the 5-year survival rate for metastatic ovarian cancer patients is still lower than 30%. Novel strategies are therefore urgently needed to complement classical treatments for this malignancy. Recently, leukocytes in the ovarian cancer microenvironment such as regulatory T cells and immature pro-angiogenic/tolerogenic myeloid cells have been demonstrated to play a fundamental role in tumor progression. This review focuses on our recent understanding of the potential of eliminating and/or modulating the phenotype of these leukocytes in vivo and in situ as a novel intervention to complement standard ovarian cancer treatments. The significant effects of targeting these crucial microenvironmental players on cancer vascularization, local tumor growth, distal metastatic spreading and spontaneous anti-tumor immune responses are discussed.

Figure 1

The inflammatory microenvironment of ovarian carcinoma. Through the production of cytokines such as IL-10 and TGFβ, and enzymes like indoleamine 2,3-dioxygenase (IDO) and arginase (ARG), ovarian tumors can directly restrain the cytotoxic activity of tumor-infiltrating T cells (TIL). In addition, tumor cells secrete cytokines such as β-defensins, MCP-1 and hypoxia-induced VEGF, which recruit, sequester and prevent the maturation of myeloid phagocytes at different stages of differentiation. These myeloid leukocytes spontaneously engulf tumor antigens but express surface determinants such as PD-L1 and B7-H4, and secrete enzymes such as ARG that, globally, abrogate the anti-tumor function of antigen-specific cytotoxic TILs. Immunosuppressive regulatory T cells (Treg) that inhibit TIL activity via IL-10. TGFβ and CTLA4 are also recruited to the tumor microenvironment, or are generated in response to signals derived from myeloid suppressive cells in situ. Myeloid leukocytes also contribute to tumor vascularization at least by secreting pro-angiogenic mediators and digesting the extracellular matrix, likely providing additional direct structural support for the deposition of sprouted endothelial cells. Matrix metalloproteinases (MMPs) and other growth factors also promote tumor growth and dissemination.