Lymphocyte Function in Tertiary Lymphoid Structures Predicts Hepatocellular Carcinoma Outcome.

Area of Science:

• Immunology
• Oncology
• Pathology

Background:

• Tertiary lymphoid structures (TLS) are increasingly recognized for their association with patient outcomes in hepatocellular carcinoma (HCC).
• The heterogeneity of cellular composition within TLS and its impact on overall survival (OS) in HCC remain underexplored.
• Understanding TLS characteristics is crucial for predicting HCC prognosis and developing immunotherapies.

Purpose of the Study:

• To investigate the relationship between TLS presence, maturation, cellular composition, and immune cell infiltration in HCC.
• To determine the prognostic significance of TLS features and their association with patient overall survival (OS).
• To explore the expression of immune checkpoint molecules within TLS and their correlation with TLS characteristics.

Main Methods:

• Multiplex immunofluorescence was used to analyze cancer tissues from 150 HCC patients.
• TLS presence, maturation status, and cellular composition (T cells, B cells) were assessed.
• Immune cell infiltration, proliferation markers (e.g., activation-induced cytidine deaminase, CD45RO), and immune checkpoint molecules (CTLA-4, PD-1, PD-L1, LAG-3) were quantified.

Main Results:

• TLS were detected in 47.3% of HCC cases and correlated with higher intratumoral lymphocyte infiltration.
• The presence of TLS and a higher proportion of mature TLS were significantly associated with better prognosis (P = .013 and P = .03, respectively).
• Intra-TLS lymphocyte proliferation mirrored intratumoral proliferation. High proportions of activated B cells and CD8+ T cells predicted improved OS, while specific B cell populations correlated with poorer OS. Reduced CTLA-4+ cells were noted in TLS-negative tumors.

Conclusions:

• TLS presence is linked to improved overall survival in HCC patients.
• TLS exhibit significant heterogeneity in maturation and cellular composition, influencing prognostic significance.
• TLS characteristics, including lymphocyte function and composition, can either promote or hinder anti-tumor immunity, impacting HCC patient outcomes.