Clinical Value of the PD-1/PD-L1/PD-L2 Pathway in Patients Suffering from Endometriosis

Abstract

The interaction between dendritic cells (DCs) and T cells mediated by the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1)/programmed cell death ligand 2 (PD-L2) pathway is the most important point in regulating immunological tolerance and autoimmunity. Disturbances in the quantity, maturity, and activity of DCs may be involved in the implantation and growth of endometrial tissue outside the uterus in endometriosis (EMS). However, little is known about the role of the immune checkpoint pathways in EMS. In our study, we examined the expression of PD-L1/PD-L2 on myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in the peripheral blood (PB) and peritoneal fluid (PF) of both EMS patients (n = 72) and healthy subjects (n = 20) via flow cytometry. The concentration of soluble PD-L1 and PD-L2 in the plasma and PF of EMS patients and the control group were determined using ELISA. We demonstrated an elevated percentage of mDCs, mDCs and pDCs with the PD-L1or PD-L2 expression, and a higher concentration of the soluble forms of PD-L1 and PD-L2 in the PF than in the plasma of EMS patients. We conclude that the peritoneal cavity environment and the PD-1/PD-L1/PD-L2 axis may play an important role in the modulation of immune response and the development and/or progression of EMS.

Expression of Gal-9 on Dendritic Cells and Soluble Forms of TIM-3/Gal-9 in Patients Suffering from Endometriosis

“…Women with EMS are noted to have altered peripheral and peritoneal cells activity, including the reduced cytotoxicity of the NK cells or decreased T cell reactivity, which lead to the failure in removing fragments of the endometrium from the peritoneal cavity and induces excessive local inflammation [ 25 ]. In our previous research study, we observed a higher frequency of mDCs and pDCs with PD-L1 and PD-L2 expression in the PF of patients with EMS [ 8 ]. In the current study, we explored the expression of Gal-9 on the mDCs and pDCs in both the systemic and local peritoneal environment of EMS patients.…”

“…The key features of EMS include the presence of an increased PF volume with chronic peritoneal inflammation, disturbances of immune cells, secreted cytokines, and growth factors, which are critical for the survival of ectopic endometrial implants [ 42 ]. In our previous research study, we showed an accumulation of mDCs, mDCs, and pDCs with PD-L1 and PD-L2 expression, in the PF of EMS patients [ 8 ]. In the present study, we observed the accumulation of mDCs-Gal-9 + , pDCs-Gal-9 + , and a soluble form of Gal-9 and TIM-3 in the PF of EMS patients in comparison to the periphery ( Figure 10 ).…”

“…However, the mechanism of the transition is still unknown [ 6 , 7 ]. The disturbances in the quantity, maturity, and activity of DCs subsets may be involved in the implantation and growth of endometrial tissue outside the uterus by the non-efficient clearing of endometrial cells, the induction of tolerance, and/or immunosupression [ 8 ].…”

“…A growing body of evidence focuses on the implication of immune checkpoints (ICPs) such as PD-1/PD-L1/PD-L2 in cancer development and also in EMS [ 8 , 9 , 10 , 11 , 12 ]. ICPs are crucial in controlling numerous biological processes, as well as maintaining the balance between the immune response and the tolerance of self-tissue in healthy conditions.…”

“…Co-inhibitory receptors may promote anergy in T lymphocytes, hamper T cell activation, and have an impact on the ability to prime T cells by antigen-presenting cells (APCs) or the secretion of various cytokines by T cells [ 13 ]. In our previous paper, we evaluated the role of the PD-1/PD-L1/PD-L2 pathway in the pathogenesis of EMS [ 8 ]. Despite significant advances in the field of the immunological aspects of endometriosis, little is known about the role of the T cell immunoglobulin and mucin domain-containing protein/galectin-9 (TIM-3/Gal-9) pathway in this disease.…”