Cytoplasmic but not nuclear cleaved gsdmd expression in live macrophages and DLBCL cells marks proinflammatory cognate interactions rather than pyroptosis and predicts better patient survival in DLBCL

Abstract Background: Pyroptosis is a form of programmed cell death characterized by cleavage of gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and release of pro-inflammatory cytokines. Its pro-inflammatory potential has garnered significant research attention in recent years but has not been studied in lymphoma. Patients and Methods: We performed immunohistochemistry for cleaved GSDMD (n-terminal) in two large cohorts of diffuse large B-cell lymphoma (DLBCL) with multiplex fluorescent IHC (mfIHC) data, and analyzed for prognostic and immune impact. Results: Cleaved GSDMD was frequently expressed in DLBCL, and only the cytoplasmic (versus nuclear) form of expression correlated with significantly better patient survival in two DLBCL cohorts. To understand the expression at the single-cell level, we examined mfIHC results, which revealed that GSDMD+cells were tumor or immune cells, and varied in Ki-67, BCL2, and MYC expression. Cases with cytoplasmic cleaved GSDMD expression had higher mean and median levels of CD38+ (activated) M1 macrophages in two cohorts and lower PD-1/PD-L1 expression, as well as phenotypes of cognate interactions between live activated M1 macrophages, DLBCL cells, and T cells in spatially resolved immune landscape by mfIHC. In contrast, phagocytosis of pyroptotic lymphoma cells by M2 macrophages and cell death of T cells were observed in cases with predominantly nuclear form of cleaved GSDMD expression. Bulk gene expression profiling analysis identified a large proportion of RNA genes upregulated in DLBCLs with cytoplasmic cleaved GSDMD expression, and deconvolution analysis found decreased frequency of the “Inflammatory” lymphoma microenvironment (LME) subtype, increased frequency of cell states and ecotypes with favorable prognostic associations, and decreased frequency of T cell exhaustion states. Summary: Analysis of pyroptosis-inducing cleaved GSDMD (n-terminal) expression in a large number of DLBCL patients revealed dinstinctive cytoplasmic and nuclear expression patterns in live and pyroptotic cells associated with different prognostic and immune effects. Cytoplasmic cleaved GSDMD expression is a marker of cognate interactions between live cells (e.g., activated M1 macrophages) associated with adaptive responses and favorable prognostic effects, whereas nuclear cleaved GSDMD expression is associated with immunosuppressive mechanisms, including T cell death and phagocytosis by M2 macrophages.

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-7079
Primary Topic
Inflammasome and immune disorders
Type
article
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article

Cytoplasmic but not nuclear cleaved gsdmd expression in live macrophages and DLBCL cells marks proinflammatory cognate interactions rather than pyroptosis and predicts better patient survival in DLBCL

Karen Dybkær, Weina Chen, Ken H. Young, Govind Bhagat et al.
Blood
Inflammasome and immune disorders
article

Cytoplasmic but not nuclear cleaved gsdmd expression in live macrophages and DLBCL cells marks proinflammatory cognate interactions rather than pyroptosis and predicts better patient survival in DLBCL

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, Chang Wang, Fenghuang Zhan, Santiago Montes‐Moreno, Shanxiang Zhang, Harry Nunns, Yong Li, Xue Kong, Michael Moeller
article en

Abstract

Abstract Background: Pyroptosis is a form of programmed cell death characterized by cleavage of gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and release of pro-inflammatory cytokines. Its pro-inflammatory potential has garnered significant research attention in recent years but has not been studied in lymphoma. Patients and Methods: We performed immunohistochemistry for cleaved GSDMD (n-terminal) in two large cohorts of diffuse large B-cell lymphoma (DLBCL) with multiplex fluorescent IHC (mfIHC) data, and analyzed for prognostic and immune impact. Results: Cleaved GSDMD was frequently expressed in DLBCL, and only the cytoplasmic (versus nuclear) form of expression correlated with significantly better patient survival in two DLBCL cohorts. To understand the expression at the single-cell level, we examined mfIHC results, which revealed that GSDMD+cells were tumor or immune cells, and varied in Ki-67, BCL2, and MYC expression. Cases with cytoplasmic cleaved GSDMD expression had higher mean and median levels of CD38+ (activated) M1 macrophages in two cohorts and lower PD-1/PD-L1 expression, as well as phenotypes of cognate interactions between live activated M1 macrophages, DLBCL cells, and T cells in spatially resolved immune landscape by mfIHC. In contrast, phagocytosis of pyroptotic lymphoma cells by M2 macrophages and cell death of T cells were observed in cases with predominantly nuclear form of cleaved GSDMD expression. Bulk gene expression profiling analysis identified a large proportion of RNA genes upregulated in DLBCLs with cytoplasmic cleaved GSDMD expression, and deconvolution analysis found decreased frequency of the “Inflammatory” lymphoma microenvironment (LME) subtype, increased frequency of cell states and ecotypes with favorable prognostic associations, and decreased frequency of T cell exhaustion states. Summary: Analysis of pyroptosis-inducing cleaved GSDMD (n-terminal) expression in a large number of DLBCL patients revealed dinstinctive cytoplasmic and nuclear expression patterns in live and pyroptotic cells associated with different prognostic and immune effects. Cytoplasmic cleaved GSDMD expression is a marker of cognate interactions between live cells (e.g., activated M1 macrophages) associated with adaptive responses and favorable prognostic effects, whereas nuclear cleaved GSDMD expression is associated with immunosuppressive mechanisms, including T cell death and phagocytosis by M2 macrophages.

BloodVol. 146(Supplement 1)
University of Verona (IT), Cedars-Sinai Medical Center (US), Toyota Motor Corporation (Switzerland) (CH), Houston Methodist (US), Northwell Health (US), Nebraska Medical Center (US), Mayo Clinic (US), NewYork–Presbyterian Hospital (US), Emory University (US), The University of Texas at San Antonio Health Science Center (US), Duke University (US), Baylor College of Medicine (US), Columbia University Irving Medical Center (US), Aalborg University Hospital (DK), Odense University Hospital (DK), University Hospital of Basel (CH), Hospital Base (CL), Marqués de Valdecilla University Hospital (ES), Methodist Hospital (US), Fundación Marques de Valdecilla (ES), Community Health Systems - Lutheran Hospital (US), Duke Medical Center (US), Methodist Hospital (US), NeoGenomics (United States) (US), Wake Forest University (US), University of Colorado Anschutz Medical Campus (US), University of Nebraska Medical Center (US), University of Arkansas for Medical Sciences (US), The University of Texas Southwestern Medical Center (US), Aalborg University (DK), University of Colorado Denver (US)
Openalex Percentile: Top 65%
Inflammasome and immune disorders
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