Abstract
Endometriosis is a common, benign, and hormone-dependent gynaecological disorder that displays altered immunoinflammatory profiles. Myeloid-derived suppressor cells (MDSCs) suppressed immunosurveillance in endometriosis in human and mouse model. Receptor tyrosine kinase inhibitor Sunitinib can induce MDSC apoptosis and suppress the progression of cancer. However, the effects of Sunitinib on MDSCs in endometriosis and the underlying mechanism are not clear. In this study, we employed an animal study of the endometriosis model in mice for treatment of Sunitinib. After syngeneic endometrium transplantation and treatment, endometriotic lesion volume, weight, and histology were compared. Peritoneal fluid, peripheral blood, and bone marrow MDSC subsets and their molecular signaling were monitored by flow cytometry. Peritoneal cytokines were assayed by ELISA. The gene expression profiles of isolated CD11b+Ly6G+Ly6Clo cells were studied by RNA sequencing. We found that Sunitinib significantly decreased the endometriotic lesion size and weight after 1 and 3 weeks, and decreased p-STAT3 activation in MDSCs after 1 week of treatment. In the first week, Sunitinib specifically increased the G-MDSC population in peritoneal fluid but the isolated CD11b+Ly6G+Ly6Clo MDSCs after Sunitinib treatment were presented as mature polynuclear MDSCs, while the control group had immature mononuclear MDSCs. Importantly, we found Sunitinib differentially suppressed gene expressions of immunosuppressive function and differentiation in peritoneal G-MDSCs. Apelin signaling pathway associated genes and inflammation related genes were upregulated, and amino acid metabolism regulator genes were downregulated in bone marrow G-MDSCs. For endometriotic lesions, the PPARG gene governing glucose metabolism and fatty acid storage, which is important for the development of endometriosis was upregulated. In conclusion, Sunitinib inhibited endometriotic lesions, by promoting peritoneal fluid MDSCs maturation and inhibiting the immunosuppressive function. These findings suggest that Sunitinib changed the immune microenvironment and inhibited the development of endometriosis, which has potential therapeutic effects as novel immunotherapy to promote MDSCs maturation, differentiation, and metabolism for the treatment of endometriosis.
Highlights
Endometriosis is a common, benign, and hormone-dependent gynaecological disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity
G-Myeloid-derived suppressor cells (MDSCs) and monocytic MDSCs (M-MDSC) populations were very low and showed no significant difference between groups in baseline 1 day before the Sunitinib and vehicle treatment (Figure 2A)
After 1 day of treatment, granulocytic MDSCs (G-MDSC) was significantly increased in the Sunitinib group when compared with control, M-MDSC remained low and no significant change (Figure 2B)
Summary
Endometriosis is a common, benign, and hormone-dependent gynaecological disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity. It is one of the main causes of pelvic pain, menstrual disorders, and infertility in reproductive women, affecting around 10% of women of reproductive age [1], but it is still under-diagnosed due to the requirement of surgical and/or pathological diagnosis. It is hypothesized that women with endometriosis have a defective immune system that is not able to recognize and perform the proper response in defending the endometrial deposits in the ectopic site [4]. This promotes the spread of endometrial cells and favors angiogenesis, tissue adhesion, and induces inflammation to promote the growth and development of endometriosis [5]
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