Immune pathway through endometriosis to ovarian cancer

Abstract

Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.

Keywords: Endometriosis; Endometriosis-associated ovarian cancers; Immune response; Immunotherapy; Ovarian neoplasms.

Figure 1

Depiction of immune surveillance evasion mechanisms in endometriosis. A: Illustration of FAS/FASL-mediated apoptosis in cytotoxic lymphocytes and TNF-α-induced ectopic endometrial cell apoptosis resistance; B: Key molecular factors contributing to dysregulated apoptosis signaling in endometriosis. CD8+ T cell: Cytotoxic T-cells; ECC: Ectopic Endometrial Cells; Erβ: Estrogen receptor β; FAS (CD95): Cluster of Differentiation 95; FASL: FAS Ligand; IL-1β: Interleukin-1β; IL-8: Interleukin-8; MΦ: Macrophage; NCOA-1: Nuclear receptor coactivator 1; NK cell: Natural killer cell; TNF-α: Tumor necrosis factor-alpha.

Figure 2

Overview of immune dysregulation similarities between on endometriosis and ovarian cancer. IL-1: Interleukin-1; IL-1B: Interleukin-1β; IL-4: Interleukin-4; IL-6: Interleukin-6; IL-8: Interleukin-8; IL-10: Interleukin-10; E2: Prostaglandin E2; ER-a: Estrogen Receptor Alpha; M1/M2: Macrophages; NK: Natural killer cell; TAM: Tumor-associated macrophages; Th1/Th2/Th17: T helper cells; TNF: Tumor Necrosis Factor; TNF-a: Tumor Necrosis Factor Alpha; TNF-B: Tumor Necrosis Factor Beta; ROS: Reactive oxygen species; VEGF: Vascular endothelial growth factor.

Figure 3

Some of the current immunotherapy approaches of treatment to ovarian cancer. Anti-CTLA-4: Cytotoxic T-Lymphocyte Associated Protein 4 Antibody; Anti-PD1: Programmed Cell death Protein 1 Antibody; Anti PD-L1: Programmed Death-ligand 1 Antibody; CAR-T cells: Chimeric Antigen Receptor-T cells; PARP: Poly Adenosine Diphosphate-Ribose Polymerase; PD-1: Programmed Cell death Protein 1; PD-L1: Programmed Death-ligand 1.

Figure 4

Illustration of anti-CD47-based immunotherapy. CD47 is a glycoprotein that is very present in the tumor environment and exerts its inhibitory activity by binding to its counter-receptor, the signal regulatory protein-α (SIRPα), expressed in macrophages. It reduces phagocytosis by these, which culminates in the progression of the tumor microenvironment. It is highly expressed patients with endometriosis. A: CD47 binding to SIRPα inhibits phagocytosis; B: Anti-CD47 blocks the binding between CD47 and SIRPα, allowing phagocytosis to occur. Anti-CD47: Integrin-associated protein Antibody; CD47: Integrin-associated protein; MΦ: Macrophage; OC cells: Ovarian Cancer cells; SIRPα: signal regulatory protein alpha.

Figure 5

Illustration of anti-CSF-1R-based immunotherapy. The colony-stimulating factor-1 receptor (CSF-1R) is a receptor that exists in several human cells during homeostasis, but is overexpressed in tumor-associated macrophages in ovarian cancer. The use of a monoclonal antibody directed at blocking CSF-1R in cancer patients, aims to manipulate the activity of TAMs, reducing tumor-associated macrophages in patients, as well as an increase in the levels of TCD8/CD4 cells in animal models. Anti-CSF-1R: Colony-Stimulating Factor 1 receptor Antibody CSF-1: Colony-Stimulating Factor 1; CSF-1R: Colony-Stimulating Factor 1 receptor; M2 TAM Φ: Tumor-associated macrophages M2; OC cell: Ovarian Cancer cells; TAM Φ: Tumor-associated macrophages.