Ferritin heavy chain 1 expression is correlated with plasma cell exhaustion and acts as a prognostic correlative marker in hepatocellular carcinoma.

BACKGROUND: Immunotherapy has emerged as a breakthrough in cancer treatment; however, the functional status of B lineage cells within the tumor microenvironment (TME) remains poorly characterized. OBJECTIVE: This study systematically profiles the heterogeneity and dysfunctional exhausted state of plasma cells in the hepatocellular carcinoma (HCC) TME, and screens molecular signatures correlated with plasma cell exhaustion. METHODS: B cell subtypes were identified from a single-cell RNA sequencing (scRNA-seq) dataset comprising 10 untreated patients with primary HCC. Gene expression profiling was performed using transcriptomic data from liver cancer tissues and paired paracancerous tissues. The abundance and distribution of exhausted plasma cells were quantified by immunohistochemistry and multiplex immunofluorescence staining. Furthermore, we analyzed the correlation between plasma cell-specific exhaustion markers and patient prognosis using the TCGA-LIHC cohort. RESULTS: FTH1 exhibited elevated expression in tumor-infiltrating plasma cells, and its expression level was significantly correlated with the exhausted phenotype of tumor-resident plasma cells. Kaplan-Meier survival analysis revealed that patients with high FTH1 expression had significantly shorter overall survival compared to those with low FTH1 expression (P = 0.0005). Importantly, we observed a significant positive correlation between FTH1 (a molecular signature correlated with plasma cell exhaustion) and the canonical T cell exhaustion marker PD-1 in HCC tumor tissues (P = 0.01). CONCLUSION: This study systematically profiles the molecular landscape of dysfunctional plasma cells within the HCC TME, confirms a correlation between FTH1 overexpression and plasma cell exhaustion, and provides correlative evidence to support further research on liver cancer immunotherapy targeting plasma cell immunity.