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

Abstract

Pyroptosis is critical for macrophages against pathogen infection, but its role and mechanism in cancer cells remain 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 tumor necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing gasdermin C (GSDMC) gene transcription. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8, and GSDMC are required for macrophage-derived TNFα-induced tumor 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/Caspas-8 mediates non-canonical pyroptosis pathway in cancer cells, causing tumor necrosis.

Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

“…Similar to other GSDMs, the N-terminal domain of GSDMC (GSDMC-NT) was able to induce pyroptosis in human 293T cells ( Ding et al, 2016 ). Recently, Hou et al (2020) revealed that GSDMC could be specifically cleaved by caspase-8, switching TNF-α-induced apoptosis to pyroptosis in breast cancer cells. They found that caspase-6 could also activate GSDMC.…”

“…STAT3 could be activated by phosphorylation at Tyr 705 (STAT3-Y705) in response to hypoxia ( Pawlus et al, 2014 ). Under hypoxia, STAT3-Y705 interacted with the important immune-checkpoint programmed death-ligand 1 (PD-L1) and favored its nuclear translocation, hence enhancing GSDMC transcription ( Hou et al, 2020 ). GSDMC was then cleaved by caspase-8 in breast cancer cells treated with TNF-α.…”

Switching from Apoptosis to Pyroptosis: Gasdermin-Elicited Inflammation and Antitumor Immunity

“…Hence, like GSDMD, other GSDM members have been expected to execute pyroptotic cell death after being processed by proteases at the linker region. Indeed, recent studies have shown that proteolytic activation of GSDME, GSDMB, and GSDMC by certain caspases and granzymes can lead to necrotic cell death ( Figure 2 ) [ 25 , 26 , 27 , 28 , 29 , 30 ]. The Nomenclature Committee on Cell Death has proposed to define pyroptosis as depends on the formation of plasma membrane pores by members of the GSDM family, often (but not always) as a consequence of inflammatory caspase activation [ 1 ].…”

“…Given the pro-inflammatory properties of regulated necrosis, it is worth considering whether non-apoptotic cell death pathways described recently are involved in traditional ICD induction. Of note, in a recent study, GSDMC-dependent pyroptosis occurred in cancer cells after treatment with anthracyclines, such as doxorubicin and epirubicin that are well-known ICD inducers, but not with most other chemotherapy drugs tested [ 29 ]. These anthracyclines induced the expression of GSDMC and activation of caspase-8 simultaneously, resulting in proteolytic activation of GSDMC by caspase-8, whereas most other drugs only induced GSDMC expression.…”

“…Although expression levels of GSDME and GSDMB were positively correlated with clinical benefit in several kinds of cancers, increased GSDMB expression was associated with poor clinical outcome in breast cancer [ 28 , 30 , 64 , 74 , 75 ]. Also, upregulation of GSDMC was observed in breast cancer, which was correlated with poor survival [ 29 ]. That is, GSDMs may also have pro-tumor effects.…”