Gasdermin D 限制 PD-L1 检查点阻断时的抗肿瘤免疫。
Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade.
机构信息
Department of Immunology, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Gusu School, Nanjing Medical University, Nanjing 211166, China.
Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China.
出版信息
Cell Rep. 2022 Oct 25;41(4):111553. doi: 10.1016/j.celrep.2022.111553.
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.
肿瘤微环境（TME）需要先天和适应性免疫细胞的合作，这些细胞影响肿瘤的进展和免疫治疗。半胱氨酸天冬氨酸蛋白酶激活的gasdermins 促进肿瘤死亡并促进抗肿瘤免疫。免疫细胞中的细胞焦亡如何影响 TME 尚不清楚。TME 中 gasdermin D（GSDMD）的表达在抗原呈递细胞（APC）中高度表达，并与免疫检查点特征相关。通过 GSDMD 的条件性缺失，我们证明 TME APC 中的 GSDMD 在 PD-L1 抑制期间限制抗肿瘤免疫。APC 中 GSDMD 的缺失增强了干扰素刺激基因（ISGs），从而以 cGAS 依赖性方式促进 CD8 T 细胞的激活。此外，抑制 GSDMD 介导的细胞焦亡和 PD-L1 的药物抑制可改善抗肿瘤免疫，突出了将 GSDMD/PD-L1 抑制作为免疫治疗的一种治疗策略的潜力。
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