Identification of pyroptosis-related signature and development of a novel prognostic model in diffuse large B-cell lymphoma.

PURPOSE: Emerging evidence suggests that pyroptosis plays an essential role in the development and progression of multiple cancers. However, the role of pyroptosis remains elusive in diffuse large B-cell lymphoma (DLBCL). METHODS: The expression profile data of DLBCL and normal samples of pyroptosis-related genes (PRGs) were analyzed, and the clinical characteristics of DLBCL patients were further investigated. A prognostic model was established using LASSO-Cox regression analysis. The expression of these PRGs was validated by qRT-PCR in DLBCL cell lines. Cell proliferation assay and flow cytometry were utilized to explore the impact of pyroptosis inhibitor (disulfiram, DSF) combined with PD1/PD-L1 inhibitor (BMS1166) on DLBCL cell proliferation. RESULTS: Most PRGs were dysregulated in DLBCL samples and associated with overall survival (OS). Six PRGs were selected to construct a prognostic risk score model. The qRT-PCR analysis revealed that CASP8, CASP9, NLRP1, NLRP6, and TIRAP are downregulated, while SCAF11 was significantly upregulated in DLBCL cell lines. This prognostic model divided DLBCL patients into low-risk and high-risk groups. Patients in the low-risk group exhibited lower mortality and longer OS than those in the high-risk group. The ROC curve and nomogram demonstrated this model's excellent predictive performance. GO and KEGG enrichment indicated that the differentially expressed genes (DEGs) between subgroups were associated with cellular protein modification processes and JAK-STAT signaling pathway regulation. Moreover, the risk score was correlated with the immune profile. Cell proliferation assay and flow cytometry further validated the synergistic anti-tumor effects of DSF and BMS1166 on DLBCL cells. CONCLUSION: In summary, we developed a comprehensive prognostic model based on PRGs characteristics, which accurately predicted the prognosis of DLBCL patients. Pyroptosis-targeting coupled with immunotherapies would be a promising therapeutic strategy for DLBCL.