Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer
Abstract Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CP...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06301-1 |
| _version_ | 1797413880452874240 |
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| author | Shourong Wang Yao Liu Huimin Xiao Zhongshao Chen Xiaohang Yang Jingjing Yin Yingwei Li Cunzhong Yuan Shi Yan Gang Chen Qinglei Gao Beihua Kong Chaoyang Sun Kun Song |
| author_facet | Shourong Wang Yao Liu Huimin Xiao Zhongshao Chen Xiaohang Yang Jingjing Yin Yingwei Li Cunzhong Yuan Shi Yan Gang Chen Qinglei Gao Beihua Kong Chaoyang Sun Kun Song |
| author_sort | Shourong Wang |
| collection | DOAJ |
| description | Abstract Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment. |
| first_indexed | 2024-03-09T05:24:23Z |
| format | Article |
| id | doaj.art-78f123d587054a5e9473947f91b46dbd |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-09T05:24:23Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-78f123d587054a5e9473947f91b46dbd2023-12-03T12:38:03ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141111410.1038/s41419-023-06301-1Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancerShourong Wang0Yao Liu1Huimin Xiao2Zhongshao Chen3Xiaohang Yang4Jingjing Yin5Yingwei Li6Cunzhong Yuan7Shi Yan8Gang Chen9Qinglei Gao10Beihua Kong11Chaoyang Sun12Kun Song13Department of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong UniversityAbstract Ovarian cancer is resistant to immune checkpoint blockade (ICB) treatment. Combination of targeted therapy and immunotherapy is a promising strategy for ovarian cancer treatment benefit from an improved immune microenvironment. In this study, Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) cohorts were used to screen prognosis and cytotoxic lymphocyte infiltration-associated genes in upregulated genes of ovarian cancer, tissue microarrays were built for further verification. In vitro experiments and mouse (C57/BL6) ovarian tumor (ID8) models were built to evaluate the synergistic effect of the combination of SF3B1 inhibitor and PD-L1 antibody in the treatment of ovarian cancer. The results show that SF3B1 is shown to be overexpressed and related to low cytotoxic immune cell infiltration in ovarian cancer. Inhibition of SF3B1 induces pyroptosis in ovarian cancer cells and releases mitochondrial DNA (mtDNA), which is englobed by macrophages and subsequently activates them (polarization to M1). Moreover, pladienolide B increases cytotoxic immune cell infiltration in the ID8 mouse model as a SF3B1 inhibitor and increases the expression of PD-L1 which can enhance the antitumor effect of αPDL1 in ovarian cancer. The data suggests that inhibition of SF3B1 improves the immune microenvironment of ovarian cancer and synergizes ICB immunotherapy, which provides preclinical evidence for the combination of SF3B1 inhibitor and ICB to ovarian cancer treatment.https://doi.org/10.1038/s41419-023-06301-1 |
| spellingShingle | Shourong Wang Yao Liu Huimin Xiao Zhongshao Chen Xiaohang Yang Jingjing Yin Yingwei Li Cunzhong Yuan Shi Yan Gang Chen Qinglei Gao Beihua Kong Chaoyang Sun Kun Song Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer Cell Death and Disease |
| title | Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer |
| title_full | Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer |
| title_fullStr | Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer |
| title_full_unstemmed | Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer |
| title_short | Inhibition of SF3B1 improves the immune microenvironment through pyroptosis and synergizes with αPDL1 in ovarian cancer |
| title_sort | inhibition of sf3b1 improves the immune microenvironment through pyroptosis and synergizes with αpdl1 in ovarian cancer |
| url | https://doi.org/10.1038/s41419-023-06301-1 |
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