PLAC8 participates in the prognosis regulation of breast cancer by regulating the infiltration of immune cells in the tumor microenvironment

Abstract

Objective To investigate the mechanism of Placenta-specific 8 (PLAC8) in the tumor microenvironment (TME) of breast cancer. Methods Two single-cell RNA-seq datasets (GSE161529 for primary breast cancer, GSE150660 for leptomeningeal metastasis) were integrated to profile microenvironmental composition and PLAC8 expression. TISCH2 was used for cell annotation, differential expression and transcription factor enrichment of PLAC8-positive immune clusters. Tumor purity-adjusted partial correlation, survival Cox regression and immune stratified prognosis analyses based on TCGA-BRCA were conducted via TIMER. GeneMANIA and Sangerbox were adopted to construct PLAC8-centered protein interaction networks and perform Gene Ontology functional enrichment. Results Primary and metastatic lesions displayed drastically remodeled immune landscapes, with monocytes/macrophages and CD8+ T cells dominating metastatic immune compartments. PLAC8 was specifically highly expressed in tumor-infiltrating B cells, whereas malignant epithelial cells barely transcribed PLAC8 in both cohorts. PLAC8 positively correlated with cell cycle/stress transcription factors (PML, E2F4, MYC) and negatively correlated with epithelial/estrogen regulators (FOXA1, ESR1). Cox analyses verified PLAC8 upregulation as an independent favorable prognostic marker. Distinct immune-dependent prognostic patterns were observed: NKT cell protective effects were PLAC8-independent; CD8+ central memory T cell survival benefits relied on PLAC8-modulated immune networks; memory B cells and pDCs only exerted anti-tumor protective effects in high-PLAC8 tumors. Enrichment results indicated PLAC8-related transcriptional and biosynthetic programs mainly support immune cell effector activation rather than malignant progression of tumor cells. Conclusion This integrated single-cell analysis identifies B-cell-specific enrichment of PLAC8 in breast cancer TME for the first time. PLAC8 reshapes immune homeostasis via core transcriptional networks and mediates heterogeneous immune synergistic prognostic effects. These findings provide novel mechanistic insights into breast cancer immune heterogeneity and candidate biomarkers for clinical prognosis stratification and immunotherapy research.