Ferroptosis Markers Predict the Survival, Immune Infiltration, and Ibrutinib Resistance of Diffuse Large B cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common hematological malignancy in adults. Ferroptosis is an iron-dependent programmed cell death caused by lipid peroxidation. However, the potential functions of ferroptosis in the DLBCL prognosis, immune infiltration, and drug resistance remain unknown. Data of DLBCL patients were downloaded from public GEO databases and TCGA cohort. R software was used for analysis. Ferroptosis-related risk score model was constructed using LASSO Cox regression analysis. The prognosis of the model and its association with immune cells infiltration and ibrutinib-resistance were studied by single-sample gene set enrichment analysis (ssGSEA) and correlation analysis. Ferroptosis-related risk score model was constructed with 11 ferroptosis-related genes. DLBCL patients can be divided into high- or low-risk groups with this model. High-risk patients had significant shorter survival (p < 0.001). The area under curve at 3-year was 0.779. Functional enrichment analysis was mainly associated with the immune response. High score patients were positively correlated with immunosuppressive cell infiltration, including macrophages and regulatory T cells, and immunoevasion checkpoints, such as CTLA4, PD-L1, LAG-3, and TIM-3. We also found that tumors with high risk would resist to ibrutinib treatment and uncovered that acetaminophen, as a ferroptosis inducer, inhibited the defined high-risk gene expression in the ibrutinib-resistant DLBCL cell lines. Ferroptosis-related risk score model can predict the overall survival (OS) of DLBCL patients and ibrutinib resistance of ABC-DLBCL cells, which was associated with immunosuppression status within the tumor microenvironment.