An immunogenic cell death-based signature predicts prognosis and immune landscape in triple-negative breast cancer

Triple-negative breast cancer (TNBC) represents a breast cancer subtype lacking three essential biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This biological signature differentiates TNBC from other breast cancer subtypes and acts as an essential diagnostic criterion for clinical identification and constitutes essential diagnostic criteria for clinical identification. Among all subtypes of breast cancer, TNBC exhibits an exceptionally high level of aggressiveness. Its aggressive behavior and paucity of effective treatment options contribute to its notoriously poor prognosis. The immunogenic cell death (ICD) emergence has raised hopes to create fresh treatment approaches to strengthen TNBC patients' immune responses against tumors. However, the correlation between ICD and TNBC prognosis is still unclear.

By analyzing transcriptomic data through the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we discovered the differentially expressed genes (DEGs) and linked to ICD in TNBC. A prognostic model utilizing ICD was developed through LASSO regression. Then, we conducted multivariate Cox proportional hazards analysis on the identified DEGs. We used receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analysis to evaluate the model's predictive accuracy. To comprehensively evaluate the clinical relevance of the ICD signature, we investigated its associations with genomic alterations, tumor microenvironment (TME) characteristics, and therapeutic responses to both chemotherapy and immunotherapy. Furthermore, functional validation was performed using MDA-MB-231 and BT-549 through various in vitro assays, including CCK-8 proliferation tests, colony formation assays, and Transwell migration experiments to assess HEYL's biological role.

A 4-gene ICD signature (HEYL, CXCL13, GBP2, and IL22RA2) was developed and stratified TNBC patients into two categories, showing major distinctions in overall survival (OS). We found that higher-risk patients had less favorable results. Meanwhile, they usually had different TMEs with less immune cell infiltration. By contrast, the low-risk group appeared to react better to immunotherapy, as evidenced by their increased immune cell infiltration level and more favorable outcomes. Analysis via the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) uncovered that DEGs were predominantly involved in immune-related pathways, for example, the receptors on the plasma membrane. Additionally, a lower immunological phenotype score (IPS) and increased susceptibility to various chemotherapeutic medicines, including A-443,654, BAY 61-3606, and CP466722, were detected in the low-risk category. Additionally, HEYL knockdown markedly suppressed TNBC cell growth and metastatic capability, whereas its overexpression produced the opposite outcome, promoting both traits.

The prognosis and responsiveness to treatment for TNBC can be anticipated by the ICD-related gene profile, highlighting the significance of the immune microenvironment. It might provide insight into the design of tailored immunotherapies for TNBC.