Open AccessPD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis
Author(s) -
J. Hou,
Rongzhen Zhao,
Weiya Xia,
Chiung Wen Chang,
Yun You,
Jung Mao Hsu,
Lei Nie,
Yeh Chen,
Yu Chuan Wang,
Chunxiao Liu,
WeiJan Wang,
Yun Wu,
Baozhen Ke,
Jennifer L. Hsu,
Ke-Bin Huang,
Zu Ye,
Yi Yang,
Xianghou Xia,
Yintao Li,
Chia Wei Li,
Bin Shao,
John A. Tainer,
MienChie Hung
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-0575-z
Subject(s) - pyroptosis , apoptosis , cancer cell , cancer research , tumor necrosis factor alpha , microbiology and biotechnology , necrosis , programmed cell death , biology , cancer , chemistry , immunology , biochemistry , genetics
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.