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
Year: 2025
Type: conference-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.
Source: Blood
Authors: Zijun Xu-Monette, Xue Kong, Zhenming Xu, Eric Hsi, Xiaoxian Zhao, Carlo Visco, Alexandar Tzankov, Karen Dybkaer, Hui Yan, Harry Nunns, Kelly Au, Shuna Yao, Dehong Wu, Chang Wang, Alexander Xu, Zenggang Pan, Leon Bernal-Mizrachi, April Chiu, Wayne Tam, Santiago Montes-Moreno, Fenghuang Zhan, Benjamin Parsons, Youli Zu, Shanxiang Zhang, Michael Moeller, Weina Chen, Qingyan Au, Akil Merchant, Govind Bhagat, Yong Li, Ken H. Young
Institutions: Duke University, Duke Medical Center, The University of Texas at San Antonio Health Science Center, Mayo Clinic, Wake Forest University Health Sciences, Wake Forest University, University of Verona, Aalborg University Hospital, Aalborg University, NeoGenomics (United States), Cedars-Sinai Medical Center, Emory University, Northwell Health, Marqués de Valdecilla University Hospital, University of Arkansas for Medical Sciences, Gundersen Lutheran Hospital, Houston Methodist, Nebraska Medical Center, University of Nebraska Medical Center, Odense University Hospital, The University of Texas Southwestern Medical Center, NewYork–Presbyterian Hospital, Columbia University Irving Medical Center, Baylor College of Medicine
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417006470
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