Chapter Six - Myeloid-derived suppressor cells: A new emerging player in endometriosis

Endometriosis is an estrogen-dependent gynecological benign disorder affecting approximately 190 million women worldwide (Zondervan et al., 2020). It is a chronic condition characterized by the deposition and growth of endometrium-like tissue outside the uterus, notably on the ovaries, pelvic viscera and rectovaginal septum. Like eutopic endometrium, the ectopic endometrial-like tissue, commonly referred to as endometriotic tissue, is usually composed of endometrial stromal and epithelial cells. They proliferate in response to estrogens but display inappropriate resistance to progesterone (Parasar et al., 2017). Along with the menstrual cycle, endometriotic tissue sheds with bleeding potentially inducing pelvic inflammation. The foci of endometriotic tissues are usually characterized by vascularization, infiltrated sensory nerve fibers, immune cells, fibrosis, and epithelial-mesenchymal transition (EMT) (Zhang et al., 2018a).

Although the typical symptoms in women with endometriosis would commonly be pelvic pain, dysmenorrhea, and infertility, several studies have shown it is also associated with miscarriage, preterm labor, preeclampsia, ectopic pregnancy, and intrauterine growth restriction (Saraswat et al., 2017). Owing to the gold standard of laparoscopic evaluation being invasive, it would generally need 7–8 years from the onset of symptoms to confirm the diagnosis (Parasar et al., 2017). Currently, there is no cure for endometriosis. The aim of current treatments, including medical and surgical management, is to alleviate endometriosis-associated pain and/or infertility to not interfere with the patient's daily life (Johnson et al., 2017). However, these symptoms can often reoccur in around 50% of women within 2 years after surgery (Bedaiwy et al., 2017). In addition, medical treatments targeting the suppression of estrogen levels can cause unbearable side effects during long-term usage, which include insomnia, hot flashes, depression, bone loss, headache and vaginal dryness. (Gallagher et al., 2018). Due to the unsatisfactory outcomes from these treatments, the low quality of life in these women would also generate a socioeconomic impact, costing approximately $4000 per affected woman in the U.S. (Simoens et al., 2014) and £8.5 billion each year in the UK (Nnoaham et al., 2019). Herein, there is an urgent need to develop a more efficient therapy with fewer adverse effects by having a clearer understanding of the underlying mechanisms of this disease and its symptoms.

As the origin of endometriotic tissues remains controversial, several theories have been proposed to explain the etiology such as Sampson's theory, coelomic metaplasia, embryonic rest theory, lymphatic and vascular metastasis theory, stem theory, and TIAR (Tissue Injury and Repair) theory (Vercellini et al., 2014). Among these, the most widely accepted concept is Sampon's theory which presumes retrograde menstruation disseminates the endometrial cells into the peritoneal cavity through the fallopian tube (Sampson, 1927). This theory was further supported by the findings of retrograde blood in peritoneal fluid at laparoscopy during the perimenstrual time and the higher risk of developing endometriosis for women with menorrhagia (Halme et al., 1984; Koninckx et al., 2021). Yet, this single principle cannot explain why over 90% of women of reproductive age have retrograde menstruation but only 10% develop endometriosis (Koninckx et al., 2021).

With the advancement in studies to elucidate the pathogenesis, growing evidence suggested that altered immunity might be a key factor contributing to the development of endometriosis. Given the excessive production of inflammatory cytokines and abnormal immune cellular response in systematic circulation, peritoneal cavity, and foci of endometriotic lesions, endometriosis has been regarded as a chronic inflammatory disorder. In addition, due to the elevated production of a variety of autoantibodies, endometriosis has also been regarded as an autoimmune-like disease (Zhang et al., 2018a). Besides promoting the survival and implantation of endometriotic cells, the altered immune microenvironment can activate the nerve sensor to cause pain, impair folliculogenesis and endometrial receptivity resulting in infertility. Therefore, immune factors have been proposed as potential therapeutic targets for endometriosis (Zhang et al., 2018a). However, the upstream triggers leading to the aberrant alteration in the immune milieu in endometriosis remain to be elucidated. In recent years, the discovery of myeloid-derived suppressor cells (MDSCs) in endometriosis opens up a new horizon in proposing a regulatory pathway resulting in immune dysfunction, which provides a promising therapeutic target for the development of immunotherapies. In brief, MDSCs are a heterogeneous cell population of immature myeloid cells with multifaceted immunoregulatory functions that have been demonstrated in tumors for more than 50 years (Talmadge and Gabrilovich, 2013). With their association with endometriosis first reported in 2017, the understanding of the roles of MDSCs in endometriosis remains limited. Based on the findings in cancers, it may help to provide hints to related investigations in endometriosis because they share similar biological features in immune tolerance, inflammation, metastasis, vascularization, fibrosis and EMT. Herein, we aimed to review the research progress of MDSCs in endometriosis from the aspects of pathophysiology to potential clinical applications based on the relevant literature and insights from studies in cancers and autoimmune diseases.

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