The programmed death ligand 1 (PD-L1) is the preeminent immune checkpoint factor, acting through its receptor PD-1 to subdue anti-tumor immunity. Agents disrupting this interaction are used clinically against various malignancies. In their recent article in Nature Cell Biology, Hou et al. reveal a novel non-immune checkpoint function of PD-L1 to switch TNFα-induced apoptosis to pyroptosis in hypoxic cancer cells. The authors began with the recently reported observation of PD-L1 in the nucleus (nPD-L1). Using both in vitro and in vivo approaches, they found that under hypoxic conditions, phosphorylated Stat3 binds to PD-L1 and the complex translocates to the nucleus where it upregulates gasdermin C (GSDMC) expression. GSDMC is then cleaved by TNFα-activated caspase-8 to generate an N-terminal GSDMC domain that creates membrane pores and pyroptotic cell death. Further experiments with human cancer cell line xenografts in mice and clinical tumor samples confirmed that all components of this nPD-L1-mediated pyroptotic pathway are essential for tumor necrosis, including macrophage-derived TNFα. In addition, in their testing of a panel of chemotherapeutic agents, the researchers found that only the antibiotic drugs were able to trigger pyroptotic cell death. All told, this study identifies an intriguing non-immune checkpoint activity for PD-L1 and a GSDMC/caspase-8-dependent pyroptotic pathway driving tumor necrosis.
GeneTex’s HIF1 alpha antibody (GTX127309) and Gasdermin C antibody (GTX33979) were used in this excellent study. Please see the featured products or click the buttons below for more information.