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.

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SUMMARY Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.

Although complement activation and deposition have been associated with a variety of glomerulopathies, the pathogenic mechanisms by which complement directly mediates renal injury remain to be fully elucidated. Renal parenchymal tissues express a limited repertoire of receptors that directly bind activated complement proteins. We report the renal expression of the receptor for the C3 cleavage product C3a, a member of the anaphylatoxin family. C3aR is highly expressed in normal human and murine kidney, as demonstrated by immunohistochemistry and in situ hybridization. Its distribution is limited to epithelial cells only, as glomerular endothelial and mesangial cells showed no evidence of C3aR expression. The C3aR is also expressed by primary renal proximal tubular epithelial cells in vitro as demonstrated by FACS, Western blot, and RT-PCR. In vitro C3aR is functional in terms of its capacity to bind 125I-labeled C3a and generate inositol triphosphate. Finally, using microarray analysis, four novel genes were identified and confirmed as transcriptionally regulated by C3aR activation in proximal tubular cells. These studies define a new pathway by which complement activation may directly modulate the renal response to immunologic injury.

The development and progression of systemic lupus erythematosus (SLE) is strongly associated with complement activation and deposition. To characterize the role of C5a and its receptor (C5aR) in SLE, C5aR-deficient mice were backcrossed nine generations onto the lupus-like MRL lpr genetic background. Evidence is presented that C5aR modulates both renal injury and T cell responses in MRL lpr mouse. C5aR-deficient MRL lpr mice had prolonged viability, with a mean survival time of 33.0 wk compared with 22.6 wk in control mice. Renal injury was also attenuated in the C5aR ؊/؊ MRL lpr mice. At 20 wk of age C5aR ؊/؊ MRL lpr mice had a complete absence of glomerular crescents and marked reductions in glomerular hypercellularity. There was no difference in the degree of glomerular C3 deposition; however, IgG deposits were reduced in the C5aR ؊/؊ MRL lpr mice. The reduction in glomerular injury was also associated with a four-fold decrease in renal CD4 ؉ T cell infiltrates.Whereas there were modest differences in total IgG anti-dsDNA antibody titers, C5aR-deficient mice had 3.5-fold higher levels of IgG1 and 15-fold lower levels of IgG2a anti-dsDNA antibody titers compared to controls. The differences in anti-dsDNA IgG subclasses were associated with reduced CD4 ؉ Th-1 responses in the C5aR ؊/؊ MRL lpr mice, including diminished production of IL-12p70, IFN-␥, and increased expression of the Th-2 transcription factor GATA-3. These findings indicate that the C5aR plays a major role in modulating complement-dependent renal injury and T helper cell Th-1 responses in the MRL lpr mouse.