Density of tertiary lymphoid structures predict clinical outcome in hepatoblastoma.

Abstract

Background: Tertiary lymphoid structures (TLSs) have emerged as critical regulators of antitumor immunity and prognostic indicators in various malignancies. However, the distribution patterns and prognostic significance of TLSs in hepatoblastoma (HB) remain poorly understood. This study aimed to investigate the presence, distribution, and prognostic value of TLSs in HB patients following neoadjuvant chemotherapy and to explore the underlying mechanisms linking TLSs to the tumor immune microenvironment.

Methods: A total of 112 HB patients who underwent neoadjuvant chemotherapy and surgical resection at Shandong Provincial Hospital between 2015 and 2024 were retrospectively enrolled. The presence of TLSs was evaluated using hematoxylin and eosin (H&E) staining, and patients were classified into TLS-positive and TLS-negative groups. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for overall survival (OS). In addition, transcriptome data from the GEO database (GSE133039) were analyzed to construct a TLS gene signature score and explore immune-related mechanisms associated with TLS presence.

Results: TLSs were identified in 45 out of 112 hepatoblastoma patients (40.2%). Kaplan-Meier survival analysis demonstrated that TLS-positive patients had significantly longer overall survival (OS) compared to TLS-negative patients (p = 0.0017). Multivariate Cox regression analysis further confirmed the presence of TLSs as an independent favorable prognostic factor (HR = 0.061, p = 0.027). In contrast, advanced PRETEXT stage (III/IV), vascular invasion, and distant metastasis were identified as independent adverse prognostic factors, indicating that patients diagnosed at later stages tended to have a worse prognosis. Transcriptomic analysis revealed that TLS-positive tumors exhibited higher expression of antigen presentation and immune activation-related genes (e.g., HLA-DQA1, HLA-DQB1, SLAMF7), along with enriched infiltration of B cells, CD8+ T cells, and NK cells, suggesting a more active antitumor immune microenvironment.

Conclusion: The presence of TLSs is significantly associated with favorable prognosis in HB patients and may contribute to enhanced antitumor immunity by recruiting and activating cytotoxic immune cells. TLSs represent a promising prognostic biomarker and potential immunotherapeutic target for HB patients.

Impact: Tertiary lymphoid structures (TLSs) serve as a promising prognostic biomarker in hepatoblastoma (HB). Our study demonstrates that TLS-positive patients exhibit significantly prolonged overall survival. TLSs contribute to the tumor immune microenvironment by recruiting cytotoxic immune cells. These findings provide new insights into TLSs as a potential immunotherapeutic target for HB patients.