Editors' ChoiceCell death

A checkpoint for pyroptosis

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Science Signaling  27 Oct 2020:
Vol. 13, Issue 655, eabf4018
DOI: 10.1126/scisignal.abf4018

The nuclear pool of an immune checkpoint protein promotes pyroptosis and tumor necrosis downstream of TNFα.

Necrosis in areas of tumor hypoxia is associated with the accumulation of macrophages that secrete TNFα, as well as resistance to cancer treatments. Hou et al. found that the immune checkpoint protein PD-L1 switched TNFα-induced cell death from apoptosis, which does not involve inflammation, to pyroptosis, an inflammatory pathway that requires the gasdermin family of proteins (see also Blasco and Gomis). In MDA-MB-231 breast cancer cells, hypoxia induced the phosphorylation of Tyr703 in the transcription factor Stat3, which promoted its interaction with PD-L1 and the nuclear translocation of PD-L1. Reconstitution of PD-L1–deficient MDA-MB-231 cells with PD-L1 bearing a mutated nuclear export signal enhanced TNFα-induced pyroptosis, an effect that was blocked by inhibiting Stat3. In hypoxic MDA-MB-231 cells, nuclear PD-L1 and Stat3 phosphorylated at Tyr703 transcriptionally activated GSDMC, which encodes gasdermin C. TNFα induced the cleavage of GSDMC by caspase-8 to generate pore-forming, N-terminal fragments that triggered pyroptosis. Tumor necrosis in MDA-MB-231 xenografts in nude mice was decreased by expression of PD-L1 with a mutated nuclear localization signal, caspase-8 deficiency, or depletion of macrophages or TNFα and increased by overexpression of GSDMC. In this mouse tumor model and in human breast tumor samples, PD-L1 and Stat3 phosphorylated at Tyr703 were present in hypoxic tumor regions. Tumor necrosis was increased and survival was decreased in mice that were orthotopically implanted with mammary tumors generated from 4T1 cells expressing wild-type PD-L1, compared with mice implanted with 4T1 cells expressing PD-L1 with a mutated nuclear localization sequence. Antibiotic-type chemotherapeutics, such as doxorubicin, correlated with increased caspase-8 activity, GSDMC cleavage, and pyroptosis, and inhibiting caspase-8 activity reduced the pyroptosis induced by these chemotherapeutics. Thus, nuclear-translocated PD-L1 promotes GSDMC cleavage, pyroptosis, and tumor necrosis downstream of TNFα.

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