PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis

• Published in: Nature cell biology Vol. 22; no. 10; pp. 1264 - 1275
• Main Authors: Hou, Junwei, Zhao, Rongce, Xia, Weiya, Chang, Chiung-Wen, You, Yun, Hsu, Jung-Mao, Nie, Lei, Chen, Yeh, Wang, Yu-Chuan, Liu, Chunxiao, Wang, Wei-Jan, Wu, Yun, Ke, Baozhen, Hsu, Jennifer L., Huang, Kebin, Ye, Zu, Yang, Yi, Xia, Xianghou, Li, Yintao, Li, Chia-Wei, Shao, Bin, Tainer, John A., Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/51; 631/67; 631/80/82; 64/60; Animals; Antibiotics; Apoptosis; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Breast cancer; Cancer; Cancer cells; Cancer Research; Caspase-8; Cell Biology; Cell membranes; Cell Proliferation; Cellular proteins; Chemotherapy; Developmental Biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Humans; Hypoxia; Hypoxia - physiopathology; Immune checkpoint; Immunosuppressive agents; Inflammasomes; Life Sciences; Macrophages; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nuclear transport; Nuclei (cytology); PD-L1 protein; Pyroptosis; Stat3 protein; Stem Cells; Switches; Transcription; Translocation; Tumor Cells, Cultured; Tumor necrosis factor-α; Tumor-Associated Macrophages; Tumors; Xenograft Model Antitumor Assays; United States
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-020-0575-z

Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C ( GSDMC ) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis. Hou et al. show that following hypoxia PD-L1 translocates into the nucleus to enhance transcription of GSDMC, which is then cleaved and activated by caspase-8 to cause pyroptosis in cancer cells.