The Dark Side of Pyroptosis of Diffuse Large B-Cell Lymphoma in B-Cell Non-Hodgkin Lymphoma: Mediating the Specific Inflammatory Microenvironment

Wei Wang; Shi-Wen Xu; Ya Teng; Min Zhu; Qun-Yi Guo; Yuan-Wen Wang; Xin-Li Mao; Shao-Wei Li; Wen-da Luo

doi:10.3389/fcell.2021.779123

The Dark Side of Pyroptosis of Diffuse Large B-Cell Lymphoma in B-Cell Non-Hodgkin Lymphoma: Mediating the Specific Inflammatory Microenvironment

Front Cell Dev Biol. 2021 Nov 5:9:779123. doi: 10.3389/fcell.2021.779123. eCollection 2021.

Authors

Wei Wang¹, Shi-Wen Xu¹, Ya Teng¹, Min Zhu¹, Qun-Yi Guo^{2

3}, Yuan-Wen Wang^{2

3}, Xin-Li Mao^{3

4

5}, Shao-Wei Li^{3

4

5}, Wen-da Luo^{1

2

3}

Affiliations

¹ Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
² Department of Hematology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
³ Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
⁴ Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
⁵ Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is a common aggressive B-cell non-Hodgkin lymphoma (B-NHL). While combined chemotherapy has improved the outcomes of DLBCL, it remains a highly detrimental disease. Pyroptosis, an inflammatory programmed cell death, is considered to have both tumor-promoting and tumor-suppressing effects. The role of pyroptosis in DLBCL has been gradually appreciated, but its value needs further investigation. Methods: We analyzed mutations and copy number variation (CNV) alterations of pyroptosis-related genes (PRGs) from The Cancer Genome Atlas (TCGA) cohort and evaluated the differences in expression in normal B cells and DLBCL patients in two Gene Expression Omnibus (GEO) datasets (GSE12195 and GSE56315). Based on the expression of 52 PRGs, we divided 421 DLBCL patients from the GSE31312 dataset into distinct clusters using consensus clustering. The Kaplan-Meier method was used to prognosis among the three clusters, and GSVA was used to explore differences in the biological functions. ESTIMATE and single-sample gene-set enrichment analysis (ssGSEA) were used to analyze the tumor immune microenvironment (TME) in different clusters. A risk score signature was developed using a univariate survival analysis and multivariate regression analysis, and the reliability and validity of the signature were verified. By combining the signature with clinical factors, a nomogram was established to predict the prognosis of DLBCL patients. The alluvial diagram and correlation matrix were used to explore the relationship between pyroptosis risk score, clinical features and TME. Results: A large proportion of PRGs are dysregulated in DLBCL and associated with the prognosis. We found three distinct pyroptosis-related clusters (cluster A, B, and C) that differed significantly with regard to the prognosis, biological process, clinical characteristics, chemotherapeutic drug sensitivity, and TME. Furthermore, we developed a risk score signature that effectively differentiates high and low-risk patients. The nomogram combining this signature with several clinical indicators showed an excellent ability to predict the prognosis of DCBCL patients. Conclusions: This work demonstrates that pyroptosis plays an important role in the diversity and complexity of the TME in DLBCL. The risk signature of pyroptosis is a promising predictive tool. A correct and comprehensive assessment of the mode of action of pyroptosis in individuals will help guide more effective treatment.

Keywords: diffuse large B-cell lymphoma; inflammation; prognosis; pyroptosis; tumor immune microenvironment.