Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer
Abstract Background Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the eff...
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BMC
2021-10-01
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Series: | Journal of Translational Medicine |
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Online Access: | https://doi.org/10.1186/s12967-021-03073-0 |
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author | Jinyu Meng Jin Peng Jie Feng Jochen Maurer Xiao Li Yan Li Shu Yao Ran Chu Xiyu Pan Junting Li Ting Zhang Lu Liu Qing Zhang Zeng Yuan Hualei Bu Kun Song Beihua Kong |
author_facet | Jinyu Meng Jin Peng Jie Feng Jochen Maurer Xiao Li Yan Li Shu Yao Ran Chu Xiyu Pan Junting Li Ting Zhang Lu Liu Qing Zhang Zeng Yuan Hualei Bu Kun Song Beihua Kong |
author_sort | Jinyu Meng |
collection | DOAJ |
description | Abstract Background Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies. Methods Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA. Results Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells. Conclusions Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment. |
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spelling | doaj.art-ef0af30ac2c84d97b0f3cec30344ae8a2022-12-21T18:36:25ZengBMCJournal of Translational Medicine1479-58762021-10-0119111610.1186/s12967-021-03073-0Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancerJinyu Meng0Jin Peng1Jie Feng2Jochen Maurer3Xiao Li4Yan Li5Shu Yao6Ran Chu7Xiyu Pan8Junting Li9Ting Zhang10Lu Liu11Qing Zhang12Zeng Yuan13Hualei Bu14Kun Song15Beihua Kong16Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, University Hospital Aachen (UKA)Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversitySchool of Medicine, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityGynecology Oncology Key Laboratory, Qilu Hospital, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong UniversityAbstract Background Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies. Methods Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA. Results Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells. Conclusions Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.https://doi.org/10.1186/s12967-021-03073-0Ovarian cancerNiraparibPARP inhibitorsPD-L1cGAS/STING pathway |
spellingShingle | Jinyu Meng Jin Peng Jie Feng Jochen Maurer Xiao Li Yan Li Shu Yao Ran Chu Xiyu Pan Junting Li Ting Zhang Lu Liu Qing Zhang Zeng Yuan Hualei Bu Kun Song Beihua Kong Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer Journal of Translational Medicine Ovarian cancer Niraparib PARP inhibitors PD-L1 cGAS/STING pathway |
title | Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer |
title_full | Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer |
title_fullStr | Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer |
title_full_unstemmed | Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer |
title_short | Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer |
title_sort | niraparib exhibits a synergistic anti tumor effect with pd l1 blockade by inducing an immune response in ovarian cancer |
topic | Ovarian cancer Niraparib PARP inhibitors PD-L1 cGAS/STING pathway |
url | https://doi.org/10.1186/s12967-021-03073-0 |
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