Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade

Yuying Jiang; Yongbing Yang; Yingchao Hu; Rui Yang; Jiajia Huang; Yi Liu; Yuqing Wu; Sheng Li; Chunmei Ma; Fiachra Humphries; Bingwei Wang; Xi Wang; Zhibin Hu; Shuo Yang

doi:10.1016/j.celrep.2022.111553

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.

Authors

Yuying Jiang¹, Yongbing Yang¹, Yingchao Hu¹, Rui Yang¹, Jiajia Huang², Yi Liu¹, Yuqing Wu³, Sheng Li¹, Chunmei Ma¹, Fiachra Humphries⁴, Bingwei Wang⁵, Xi Wang⁶, Zhibin Hu⁷, Shuo Yang⁸

Affiliations

¹ 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.
² Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China.
³ 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 Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, National Key Clinical Department of Laboratory Medicine, Nanjing 210029, China.
⁴ Department of Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.
⁵ Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China. Electronic address: bingweiwang@njucm.edu.cn.
⁶ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: xiwang@njmu.edu.cn.
⁷ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: zhibin_hu@njmu.edu.cn.
⁸ 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. Electronic address: shuoyang@njmu.edu.cn.

PMID: 36288704
DOI: 10.1016/j.celrep.2022.111553

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.

Keywords: CP: Cancer; CP: Immunology; GSDMD; anti-tumor immunity; macrophage/DC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen*
Caspases
Interferons
Nucleotidyltransferases
Tumor Microenvironment*

Substances

B7-H1 Antigen
Caspases
Interferons
Nucleotidyltransferases