Proinflammatory GSDMD activation in live macrophages and DLBCL cells marks cognate interactions and better prognosis

Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of "Don't eat me"-signaling genes, upregulation of many RNA genes, decreased frequency of "inflammatory" lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

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Publication Details

Journal
Blood Advances
Published
2025-12-05
DOI
https://doi.org/10.1182/bloodadvances.2025017643
Citations
2
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
1.61
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article

Proinflammatory GSDMD activation in live macrophages and DLBCL cells marks cognate interactions and better prognosis

Michael Møller, Karen Dybkær, Weina Chen, Ken H. Young et al.
2 citations
Blood Advances
Inflammasome and immune disorders
1.61
article

Proinflammatory GSDMD activation in live macrophages and DLBCL cells marks cognate interactions and better prognosis

Michael Møller, Karen Dybkær, Weina Chen, Ken H. Young, Govind Bhagat, Benjamin M. Parsons, Hui Yan, Xiaoxian Zhao, Eric D. Hsi, Zijun Y. Xu‐Monette, Leon Bernal‐Mizrachi, Shuna Yao, Alexandar Tzankov, Carlo Visco, Dehong Wu, Karolyn Au, April Chiu, Zenggang Pan, Youli Zu, Wayne Tam, Qingyan Au, Alexander M. Xu, Zhenming Xu, Akil Abid Merchant, Fenghuang Zhan, Santiago Montes‐Moreno, Shanxiang Zhang, Harry Nunns, Yong Li, Xue Kong, Chang Wang
article en
2 citations

Abstract

Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of "Don't eat me"-signaling genes, upregulation of many RNA genes, decreased frequency of "inflammatory" lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

Blood AdvancesVol. 10(5)
University of Verona (IT), Atrium Health Wake Forest Baptist (US), Cedars-Sinai Medical Center (US), Gundersen Health System (US), Northwell Health (US), Mayo Clinic (US), Emory University (US), Baylor College of Medicine (US), Aalborg University Hospital (DK), Odense University Hospital (DK), SSM Health Care (US), University Hospital of Basel (CH), Zhengzhou University (CN), Southwestern Medical Center (US), Marqués de Valdecilla University Hospital (ES), Piedmont Cancer Institute (US), Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US), Methodist Hospital (US), Instituto de Investigación Marqués de Valdecilla (ES), Mayo Clinic in Arizona (US), Duke Medical Center (US), Winthrop Rockefeller Foundation (US), Henan Cancer Hospital (CN), NeoGenomics (United States) (US), Duke Cancer Institute, The University of Texas at San Antonio (US), Wake Forest University (US), Saint Louis University (US), University of Colorado Anschutz Medical Campus (US), University of Nebraska Medical Center (US), University of Maryland, College Park (US), Columbia University (US), University of Arkansas for Medical Sciences (US), The University of Texas Southwestern Medical Center (US), University of Colorado Denver (US)
Openalex Percentile: Top 14%
Inflammasome and immune disorders
1.61
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