Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis.

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.

He Y ，Hung SW ，Liang B ，Zhang R ，Gao Y ，Chu CY ，Zhang T ，Xu H ，Chung JPW ，Wang CC ... -  《Frontiers in Immunology》

MDSCs drive the process of endometriosis by enhancing angiogenesis and are a new potential therapeutic target.

Endometriosis affects women of reproductive age via unclear immunological mechanism(s). Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive and angiogenic properties. Here, we found MDSCs significantly increased in the peripheral blood of patients with endometriosis and in the peritoneal cavity of a mouse model of surgically induced endometriosis. Majority of MDSCs were granulocytic, produced ROS, and arginase, and suppressed T-cell proliferation. Depletion of MDSCs by antiGr-1 antibody dramatically suppressed development of endometrial lesions in mice. The chemokines CXCL1, 2, and 5 were expressed at sites of lesion while MDSCs expressed CXCR-2. These CXC-chemokines promoted MDSC migration toward endometriotic implants both in vitro and in vivo. Also, CXCR2-deficient mice show significantly decreased MDSC induction, endometrial lesions, and angiogenesis. Importantly, adoptive transfer of MDSCs into CXCR2-KO mice restored endometriotic growth and angiogenesis. Together, this study demonstrates that MDSCs play a role in the pathogenesis of endometriosis and identifies a novel CXC-chemokine and receptor for the recruitment of MDSCs, thereby providing a potential target for endometriosis treatment.

Zhang T ，Zhou J ，Man GCW ，Leung KT ，Liang B ，Xiao B ，Ma X ，Huang S ，Huang H ，Hegde VL ，Zhong Y ，Li Y ，Kong GWS ，Yiu AKW ，Kwong J ，Ng PC ，Lessey BA ，Nagarkatti PS ，Nagarkatti M ，Wang CC ... -  《-》

CD33(+) CD14(+) CD11b(+) HLA-DR(-) monocytic myeloid-derived suppressor cells recruited and activated by CCR9/CCL25 are crucial for the pathogenic progression of endometriosis.

Endometriosis (EM) is a chronic immunoinflammatory disease associated with an abnormal immunotolerant microenvironment. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a major role in immunosuppression in cancer, inflammation and other diseases. This paper aims to elucidate whether or not MDSCs are involved in regulating this microenvironment in EM and how this regulation occurs. Immunochemistry (IHC) and qPCR were conducted to measure CD11b and ARG1 expression in the ectopic endometrium samples from EM patients. CCL25 levels in EM PF and the expression of CCR9 on M-MDSCs were measured by ELISA. M-MDSC migration was determined towards rhCCL25, α-CCR9, α-CCL25 and EM PF through in vitro chemotaxis assay. CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs isolated from EM PBMCs were added to CD8+ T cells stimulated with α-CD3/α-CD28 antibody. After 72 hours of co-culture, proliferation was measured to rate the immunosuppressive function of M-MDSCs. Finally, levels of IL-10, GM-CSF and arginase activity in the cultured supernatants were detected. IHC and qPCR results revealed higher CD11b and ARG1 expression in EM endometrium than normal endometrium. MDSCs accumulated in the EM microenvironment, in which M-MDSCs were the predominant type. CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs expressed high CCR9 levels and were recruited through CCL25. M-MDSCs from EM PBMCs inhibited proliferation and activity in autologous T cells. rhCCL25 promoted IL-10 and GM-CSF secretion and arginase enzymatic activity in CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs. CD33+ CD14+ CD11b+ HLA-DR- M-MDSCs recruited and activated by CCR9/CCL25 play a crucial role in the pathogenic progression of endometriosis, thus providing a potential target for EM treatment.

Sun Y ，Shao J ，Jiang F ，Wang Y ，Yan Q ，Yu N ，Zhang J ，Zhang J ，Li M ，He Y ... -  《-》

The roles of polymorphonuclear myeloid-derived suppressor cells in endometriosis.

This study aimed to determine the systemic and local proportions, focal localization, and characteristics of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in endometriosis. Peripheral blood and peritoneal fluid were obtained from patients with a benign gynecologic condition (controls) or endometriosis. PMN-MDSCs were defined as CD33+HLA-DRlow/-CD14-CD15+ and monocytic (M)-MDSCs were defined as CD33+HLA-DRlow/-CD14+CD15-, and were identified using flowcytometry. Ovarian endometriotic tissues were obtained, and the expression of lectin-type oxidized low density lipoprotein receptor-1 (LOX1) as a marker of PMN-MDSCs, arginine 1 (Arg1), and matrix metalloproteinase 9 (MMP9) were detected using immunohistochemistry. Anti-Ly6G antibody was administered to endometriosis model mice, and the number and weight of the lesions were measured, and cell proliferations and apoptosis in the lesions were analyzed using Ki67 immunohistochemistry and TUNEL assay. In the peripheral blood, the proportion of PMN-MDSCs was significantly higher in endometriosis (3.20 vs 1.63 %, p < 0.05), but the proportion of M-MDSCs did not differ between the groups. In the peritoneal fluid, the proportion of PMN-MDSCs was significantly higher in endometriosis (7.82 × 10-1% vs 6.48 × 10-2%, p < 0.05), whereas the proportion of M-MDSCs did not differ between the groups. PMN-MDSCs were detected in the stromal cell layer of the endometriotic cyst wall. Double staining for LOX1 and Arg1, and LOX1 and MMP9 was confirmed. Administration of Ly6G antibody did not change the number or weight of endometriosis lesions, but significantly decreased Ki67-positive cells and increased TUNEL-positive cells in the lesions. PMN-MDSCs may contribute to the pathogenesis of endometriosis via Arg1 and MMP9 expression.

Satake E ，Koga K ，Takamura M ，Izumi G ，Elsherbini M ，Taguchi A ，Makabe T ，Takeuchi A ，Harada M ，Hirata T ，Hirota Y ，Wada-Hiraike O ，Osuga Y ... -  《-》

The mTOR signal regulates myeloid-derived suppressor cells differentiation and immunosuppressive function in acute kidney injury.

Zhang C ，Wang S ，Li J ，Zhang W ，Zheng L ，Yang C ，Zhu T ，Rong R ... -  《Cell Death & Disease》