Deletion of gasdermin D promotes granulocytic myeloid-derived suppressor cell differentiation by decreased release of mitochondrial DNA to promote tumor escape
Min Gu, Weiwei Chen, Shizhen Ding, Zhijie Lin, Qian Li, Weiming Xiao, Xiaoqin Jia, Guotao Lu, Weijuan Gong
Abstract
Gasdermin D (GSDMD), an effector molecule of cell pyroptosis, is known to be activated in various cells during inflammation. However, the patterns of GSDMD activation in immune regulatory cells such as myeloid-derived suppressor cells (MDSCs) remain unclear. In this study, we found that neutrophils in colorectal cancer (CRC) tissues exhibited reduced GSDMD transcription, as evidenced by a single-cell RNA sequencing result. Consistent with this, cleaved GSDMD expression is negatively correlated with S100A8 in CRC tissues. Additionally, CD15 + CD14 − LOX1 + cells (G-MDSCs) from the peripheral blood of CRC patients exhibited a significant reduction in GSDMD activation. Mice with ubiquitous GSDMD deficiency bred in a clean environment exhibited a notable increase in G-MDSCs. These GSDMD −/− MDSCs enhanced immunosuppressive activity by both inhibiting effector T-cell activity and promoting regulatory T-cell induction. This enhancement was also observed in GSDMD flox/flox -S100A8 Cre mice, in which GSDMD was specifically deleted in MDSCs. The tumor-promoting effects in the GSDMD −/− and GSDMD flox/flox -S100A8 Cre mice were abrogated following MDSC depletion, as shown by the use of an anti-DR5 antibody. In the absence of GSDMD, G-MDSCs showed reduced inflammasome activation and decreased production of IL-1β and IL-18. Furthermore, a significant reduction in interferon-related factor 8/7 (IRF8/7) was observed in GSDMD −/− G-MDSCs via bulk RNA sequencing analysis. After treatment with LPS/nigericin, these cells maintained mitochondrial integrity, thus impairing the mtDNA release and the downstream cGAS/STING/TBK1/IRF8/7 signaling axis activation. Reduced IRF8/7 levels were responsible for increased differentiation of GSDMD −/− G-MDSCs. Finally, treatment with a GSDMD recombinant lentivirus injected into in situ tumors significantly inhibited tumor growth and reduced G-MDSC levels, suggesting that a GSDMD-based vaccine could simultaneously exert anti-carcinoma and anti-MDSC effects.