Immune Tumor Microenvironment in Ovarian Cancer Ascites

Abstract

Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology.

Keywords: cytokines; high-grade serous carcinoma; immune cells; malignant ascites; ovarian cancer; tumor microenvironment.

Figure 1

The different origins of ovarian tumors, specifically the types of Epithelial Ovarian Carcinoma (EOC), created by Biorender.com (accessed on 26 August 2022). High-grade serous carcinoma (HGSC); Low-grade serous carcinoma (LGSC); Endometrioid carcinoma (EC); Clear cell carcinoma (CCC); Mucinous carcinoma (MC).

Figure 2

Cellular and acellular components of Malignant Ascites, created by Biorender.com (accessed on 26 August 2022) and adapted from Kim et al. [2]. MAs are composed of tumor cells (single cells or as spheroids) and non-tumor cells, including fibroblasts, mesothelial cells, endothelial cells, adipocytes, and immune cells. These types of cells communicate with each other through acellular factors, including cytokines, proteins, metabolites, and exosomes.

Figure 3

The role of Immune Cells in the tumor microenvironment, created by Biorender.com (accessed on 26 August 2022). On the left is represented the immune cells that act as tumor killers by the production of cytokines or by phagocytosis, that can destroy tumor cells, and on the right, the cells that contribute to immune suppression. TIL- Tumor Infiltrating Lymphocytes; CD8⁺ T—cytotoxic T cells; Th1—CD4⁺ helper 1 T cell; NK—Natural Killer; M1—Macrophage Anti-tumoral; N1—Neutrophil like-type 1; DC—Dendritic cell; Treg—Regulator T cell; Th2—CD4⁺ helper 2 T cell; TApDC—Tumor-Associated plasmacytoid Dendritic cell; N2—Neutrophil like-type 2; M2—Macrophage Pro-tumoral; MDSc—Myeloid-Derived Suppressor Cells.

Figure 4

The effect of cytokines in the tumor microenvironment, created by Biorender.com (accessed on 26 August 2022), adapted by Briukhovetska et al. [185]. Immune evasion and tumor progression depend on cancer cell-intrinsic and -extrinsic cytokine signaling. It is shown that OC overexpresses certain cytokines, for example, IL-6, which act in an autocrine way to upregulate glycolysis and induce metabolic reprogramming, nuclear factor kappa-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3). These pathways in change can lead to epithelial–mesenchymal transition (EMT), increased proliferation, reduced apoptosis, increased migration, and the production of cytokines, such as IL-8 and VEGF, which induces angiogenesis. However, other cytokines, such as IL-1β, IL-13, IL-17, IL-22, IL-23, and IL-35 also induce EMT and, thus, tumor progression. Tumor-secreted IL-8 stimulates the recruitment of polymorphonuclear leukocytes (PMNs) and, in association with monocytes, they differentiate into MDSCs, inhibiting Th1 responses. MDSCs, TAMs, and M2 macrophages that are polarized by Th2-type cytokines contribute to higher levels of TGF-β that form an immunosuppressive microenvironment. In sequence, TGF-β together with IL-33 promotes the differentiation of Treg cells, which have a high affinity to IL-2 receptor (IL-2R) and are a major source of IL-10 that, under chronic conditions, suppresses antitumor responses. Additionally, TGF-β with IL-6 promotes the differentiation of Th17 cells that produce IL-17 and promote more MDSC recruitment and differentiation. pSTAT3, phosphorylated STAT3; EMT transcription factors (ZEB, SNAI1, SLUG, TWIST).