Regulation of Ovarian Cancer Prognosis by Immune Cells in the Tumor Microenvironment

Abstract

It is estimated that in the United States in 2018 there will be 22,240 new cases of ovarian cancer and 14,070 deaths due to this malignancy. The most common subgroup of this disease is high-grade serous ovarian cancer (HGSOC), which is known for its aggressiveness, high recurrence rate, metastasis to other sites, and the development of resistance to conventional therapy. It is important to understand the ovarian cancer tumor microenvironment (TME) from the viewpoint of the function of pre-existing immune cells, as immunocompetent cells are crucial to mounting robust antitumor responses to prevent visible tumor lesions, disease progression, or recurrence. Networks consisting of innate and adaptive immune cells, metabolic pathways, intracellular signaling molecules, and a vast array of soluble factors, shape the pathogenic nature of the TME and are useful prognostic indicators of responses to conventional therapy and immunotherapy, and subsequent survival rates. This review highlights key immune cells and soluble molecules in the TME of ovarian cancer, which are important in the development of effective antitumor immunity, as well as those that impair effector T cell activity. A more insightful knowledge of the HGSOC TME will reveal potential immune biomarkers to aid in the early detection of this disease, as well as biomarkers that may be targeted to advance the design of novel therapies that induce potent antitumor immunity and survival benefit.

Keywords: antitumor immunity; dendritic cells; immune inhibition; immunotherapy; tumor microenvironment; tumor-associated macrophages; tumor-infiltrating lymphocytes.

Figure 1

Schematic representation of the primary immune components in the tumor microenvironment (TME). Several cell types in the TME of high-grade serous ovarian carcinoma (HGSOC) elaborate factors that can lead to immune dysregulation and inhibition of antitumor responses. The ascites of these patients is rich in TGF-β, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), and CCL22 and other factors released by contributing cell types as shown in the graphic. CCL22 (the ligand for CCR4) preferentially recruits Tregs into tumors. Exhausted CD8 T cells in tumors express PD-1 and LAG-3 and secrete low quantities of IFN-γ. Several Treg subsets exist in the TME, each bearing some of the phenotypic markers, CD4, CD8, CCR4, FoxP3, CD25, GITR, or CTLA-4, and primarily release TGF-β and IL-10. Molecules such as recepteur d’origine nantais (RON) on tumor cells are associated with invasiveness, and tumor associated antigens (TAAs) such as New York Esophageal antigen-1 (NY-ESO-1), human epidermal growth factor receptor 2 (HER-2), and Wilm’s tumor-1 (WT-1) are immunogenic targets. Immune-suppressive mechanisms in the TME that foster tumor initiation, progression, and recurrence may be reversed with combinations of conventional and novel therapies, designed to potentiate antitumor immune responses. Parameters consistent with disease improvement include CD8+ T cells secreting IFN-γ, perforin, and granzyme B, which facilitate the killing of tumor cells. Additionally, DC-secreted chemokines, such as CXCL9 and CXCL10, can recruit CD4+ and CD8+ immunocompetent T cells, and IL-16-a-cytokine secreted by T cells, macrophages, and dendritic cells, is a primary chemoattractant for CD4+T cells in ovarian cancer.