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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Main Authors: 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
Format: Article
Language:English
Published: BMC 2021-10-01
Series:Journal of Translational Medicine
Subjects:
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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