NLRP3 Inflammasome Upregulates PD-L1 in Ovarian Cancer and Contributes to an Immunosuppressive Microenvironment
Wenjing Pan, Zhaoyang Jia, Jingtong Du, Kexin Chang, Yiming Liu, Wei Liu, Xibo Zhao, Wenhua Tan
Abstract
Introduction: The NLRP3 inflammasome has been implicated in the initiation of inflammation and tumorigenesis; however, its role in epithelial ovarian cancer (EOC) remains unclear. Methods: This study employed high-throughput sequencing data, ELISA, clone formation assay, Western blot, and flow cytometric analysis to investigate the specific role of the NLRP3 inflammasome in EOC. Results: NLRP3 was highly expressed in human EOC tissues and correlated with an unfavorable prognosis. Activation of the NLRP3 inflammasome by LPS and ATP promoted EOC cell proliferation and increased IL-1 and PD-L1 levels. MCC950, a NLRP3 inflammasome blocker, reduced IL-1 and PD-L1 levels and diminished tumor-immune suppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and PD-1 + CD4 + T cells, in a murine model of ovarian cancer. This intervention also suppressed tumor growth. Conclusion: Our investigation revealed the pro-tumorigenic role of the NLRP3 inflammasome and its regulation of PD-L1 expression in EOC. Blockade of the NLRP3 inflammasome led to reduced PD-L1 expression, fewer immunosuppressive cells, and suppressed tumor growth. These findings suggest that targeting the NLRP3 inflammasome-PD-L1 axis could be a novel treatment approach for ovarian cancer. Keywords: NLRP3 inflammasome, PD-L1, immunosuppressive cells, EOC, inflammation