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 induc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.641206/full |
| _version_ | 1818741640825667584 |
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| author | Ying He Sze Wan Hung Bo Liang Ruizhe Zhang Yating Gao Ching Yan Chu Tao Zhang Hui Xu Jacqueline Pui Wah Chung Chi Chiu Wang Chi Chiu Wang Chi Chiu Wang Chi Chiu Wang |
| author_facet | Ying He Sze Wan Hung Bo Liang Ruizhe Zhang Yating Gao Ching Yan Chu Tao Zhang Hui Xu Jacqueline Pui Wah Chung Chi Chiu Wang Chi Chiu Wang Chi Chiu Wang Chi Chiu Wang |
| author_sort | Ying He |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T01:59:51Z |
| format | Article |
| id | doaj.art-ad75c2833bd24341b3ea96480e676176 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-18T01:59:51Z |
| publishDate | 2021-07-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-ad75c2833bd24341b3ea96480e6761762022-12-21T21:24:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.641206641206Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of EndometriosisYing He0Sze Wan Hung1Bo Liang2Ruizhe Zhang3Yating Gao4Ching Yan Chu5Tao Zhang6Hui Xu7Jacqueline Pui Wah Chung8Chi Chiu Wang9Chi Chiu Wang10Chi Chiu Wang11Chi Chiu Wang12Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaDepartment of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaLi Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaSchool of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaChinese University of Hong Kong–Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR ChinaEndometriosis 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.641206/fullendometriosismyeloid-derived suppressor cellsSunitinibimmunosuppressiongene expressions |
| spellingShingle | Ying He Sze Wan Hung Bo Liang Ruizhe Zhang Yating Gao Ching Yan Chu Tao Zhang Hui Xu Jacqueline Pui Wah Chung Chi Chiu Wang Chi Chiu Wang Chi Chiu Wang Chi Chiu Wang Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis Frontiers in Immunology endometriosis myeloid-derived suppressor cells Sunitinib immunosuppression gene expressions |
| title | Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis |
| title_full | Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis |
| title_fullStr | Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis |
| title_full_unstemmed | Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis |
| title_short | Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis |
| title_sort | receptor tyrosine kinase inhibitor sunitinib as novel immunotherapy to inhibit myeloid derived suppressor cells for treatment of endometriosis |
| topic | endometriosis myeloid-derived suppressor cells Sunitinib immunosuppression gene expressions |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.641206/full |
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