Chunyan Xue1, Yun Xu1, Wenfeng Ye1, Quanqin Xie2, Hongyan Gao1, Bin Xu2, Dachuan Zhang3, Jingting Jiang4. 1. Department of Tumor Biological Treatment, Soochow University, Jiangsu, Changzhou 213003, China; Department of Obstetrics and Gynecology, Soochow University, Jiangsu, Changzhou 213003, China. 2. Department of Tumor Biological Treatment, Soochow University, Jiangsu, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Jiangsu, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Jiangsu, Changzhou 213003, China. 3. Department of Tumor Biological Treatment, Soochow University, Jiangsu, Changzhou 213003, China; Pathology Department, The Third Affiliated Hospital of Soochow University, Soochow University, Jiangsu, Changzhou 213003, China. 4. Department of Tumor Biological Treatment, Soochow University, Jiangsu, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Soochow University, Jiangsu, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Jiangsu, Changzhou 213003, China. Electronic address: jiangjingting@suda.edu.cn.
Abstract
BACKGROUND: Ovarian cancer samples were studied to determine the expression of programmed death ligand-1 (PD-L1) and its relationship with prognosis, and to explore the effect and potential mechanism of a PARP inhibitor combined with PD-L1 monoclonal antibody for the treatment of ovarian cancer. MATERIALS AND METHODS: PD-L1 expression in paraffin-embedded tissues of ovarian cancer was detected by immunohistochemistry (IHC). Flow cytometry was used to detect PD-L1 expression in TILs. Furthermore, we investigated the mechanism of the upregulation of PD-L1 expression by PARP inhibitors in vitro and verified the combined effect in vivo. RESULTS: Our study demonstrated that PD-L1 expression in ovarian cancer tissues was associated with the FIGO stage (P = 0.026). OS was significantly lower in high PD-L1 expression group than in the low expression group (P = 0.0005, HR = 2.689), PD-L1 high expression (P = 0.023, HR = 2.275) and FIGO stage (P = 0.024, HR = 11.229) were independent risk factors affecting the survival and prognosis of ovarian cancer patients. Flow cytometry test suggested that PD-L1+ expression was negatively correlated with CD8+ T cell count in ovarian cancer cells (P = 0.054, r = -0.624). In vitro experiments revealed that PD-L1 expression of ovarian cancer cell lines was upregulated after intervention with PARP inhibitors through the Chk1 pathway. The results of in vivo experiments suggested that the growth volume and quality of tumors in the combination group were significantly lower than those in control group (P < 0.05). CONCLUSIONS: PARP inhibitors could induce upregulation of PD-L1 expression by promoting phosphorylation of chk1. Antagonistic PD-L1 could reverse the inhibitory effect of PARP inhibitors on CD8+T cells, and had synergistic antitumor effect with PARP inhibitors.
BACKGROUND:Ovarian cancer samples were studied to determine the expression of programmed death ligand-1 (PD-L1) and its relationship with prognosis, and to explore the effect and potential mechanism of a PARP inhibitor combined with PD-L1 monoclonal antibody for the treatment of ovarian cancer. MATERIALS AND METHODS:PD-L1 expression in paraffin-embedded tissues of ovarian cancer was detected by immunohistochemistry (IHC). Flow cytometry was used to detect PD-L1 expression in TILs. Furthermore, we investigated the mechanism of the upregulation of PD-L1 expression by PARP inhibitors in vitro and verified the combined effect in vivo. RESULTS: Our study demonstrated that PD-L1 expression in ovarian cancer tissues was associated with the FIGO stage (P = 0.026). OS was significantly lower in high PD-L1 expression group than in the low expression group (P = 0.0005, HR = 2.689), PD-L1 high expression (P = 0.023, HR = 2.275) and FIGO stage (P = 0.024, HR = 11.229) were independent risk factors affecting the survival and prognosis of ovarian cancerpatients. Flow cytometry test suggested that PD-L1+ expression was negatively correlated with CD8+ T cell count in ovarian cancer cells (P = 0.054, r = -0.624). In vitro experiments revealed that PD-L1 expression of ovarian cancer cell lines was upregulated after intervention with PARP inhibitors through the Chk1 pathway. The results of in vivo experiments suggested that the growth volume and quality of tumors in the combination group were significantly lower than those in control group (P < 0.05). CONCLUSIONS:PARP inhibitors could induce upregulation of PD-L1 expression by promoting phosphorylation of chk1. Antagonistic PD-L1 could reverse the inhibitory effect of PARP inhibitors on CD8+T cells, and had synergistic antitumor effect with PARP inhibitors.