Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade
Jiang, Yuying Yang, Yongbing Hu, Yingchao Yang, Rui Huang, Jiajia Liu, Yi Wu, Yuqing Li, Sheng Ma, Chunmei Humphries, Fiachra
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Abstract
Tumor microenvironments (TMEs) require co-operation of innate and adaptive immune cells, which influence tumor progression and immunotherapy. Caspase-activated gasdermins facilitate tumor death and promote anti-tumor immunity. How pyroptosis in immune cells affects the TME remains unclear. TME expression of gasdermin D (GSDMD) is highly expressed in antigen-presenting cells (APCs) and correlates with immune checkpoint signatures. Through conditional deletion of GSDMD, we demonstrate that GSDMD in TME APCs restricts anti-tumor immunity during PD-L1 inhibition. Loss of GSDMD in APCs enhances interferon-stimulated genes (ISGs), thereby promoting CD8+ T cell activation in a cGAS-dependent manner. Moreover, pharmacological inhibition of GSDMD-mediated pyroptosis and PD-L1 improve anti-tumor immunity, highlighting the potential of combining GSDMD/PD-L1 inhibition for immunotherapy as a therapeutic strategy.
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Jiang Y, Yang Y, Hu Y, Yang R, Huang J, Liu Y, Wu Y, Li S, Ma C, Humphries F, Wang B, Wang X, Hu Z, Yang S. Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade. Cell Rep. 2022 Oct 25;41(4):111553. doi: 10.1016/j.celrep.2022.111553. PMID: 36288704.