Abstract
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.
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Data availability
Publicly available datasets and online tools were utilized in this study. These resources could be found here: https://portal.gdc.cancer.gov/, https://www.proteinatlas.org/, https://www.ncbi.nlm.nih.gov/geo/.
Abbreviations
- DLBCL:
-
Diffuse large B-cell lymphoma
- PRGs:
-
Pyroptosis-related genes
- OS:
-
Overall survival
- DEGs:
-
Differentially expressed genes
- IPI:
-
International prognostic index
- PCD:
-
Programmed cell death
- GSDMA:
-
Gasdermin A
- GSDME:
-
Gasdermin E
- PJVK :
-
Pejvakin
- NK cells:
-
Natural killer cells
- PBMCs:
-
Peripheral blood mononuclear cells
- STR:
-
Short tandem repeat
- qRT-PCR:
-
Quantitative reverse-transcription polymerase chain reaction
- CCK-8:
-
Cell Counting Kit-8
- TCGA:
-
The cancer genome atlas
- GTEx:
-
Genotype-tissue expression project
- GEO:
-
Gene expression omnibus
- HPA:
-
The human protein atlas
- PPI:
-
Protein–protein interaction
- NHL:
-
Non-Hodgkin lymphoma
- HR:
-
Hazard ratio
- ECOG:
-
Eastern cooperative oncology group
- AUC:
-
The area under the ROC curve
- pDCs:
-
Plasma cell-like dendritic cells
- Tfh:
-
Follicular helper T cells
- Th1 cells:
-
T helper 1 cells
- TIL:
-
Tumor-infiltrating lymphocytes
- Th2:
-
T helper 2 cells
- HLA:
-
Human leukocyte antigen transmission
- LAG-3:
-
Lymphocyte activation gene-3
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Funding
This study was supported by National Natural Science Foundation (No.82270200, No.82170189, No.82070203, No.81800194, No.81770210); Key Research and Development Program of Shandong Province (No.2018CXGC1213); China Postdoctoral Science Foundation (No. 2021T1404223); Translational Research Grant of NCRCH (No.2021WWB02, No.2020ZKMB01); Shandong Provincial Natural Science Foundation (ZR2021YQ51); Taishan Scholars Program of Shandong Province; Technology Development Project of Jinan City (No. 202134034); Shandong Provincial Engineering Research Center of Lymphoma; Academic Promotion Programme of Shandong First Medical University (No. 2019QL018).
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XZ, XW, and LL designed the study. LL, YZ, RK, and CW collected data. LL conducted the experiments and data analysis. LL wrote and edited this manuscript and created figures and tables. XZ, XW, and LL reviewed and revised the manuscript. All authors read and approved the final manuscript.
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The study was performed with the approval of the Medical Ethical Committee of Shandong Provincial Hospital (reference NSFC: NO.2021–217). All samples were collected with informed consent according to the Declaration of Helsinki.
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Lv, L., Zhang, Y., Kong, R. et al. Identification of pyroptosis-related signature and development of a novel prognostic model in diffuse large B-cell lymphoma. J Cancer Res Clin Oncol 149, 12677–12690 (2023). https://doi.org/10.1007/s00432-023-05018-0
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DOI: https://doi.org/10.1007/s00432-023-05018-0