Age-associated B cells enhance tertiary lymphoid structures in the liver and promote HCC formation
A. Morsing, Kenneth Green, Signe Clausen, Camilla R. Benjaminsen, Mathilde S. Blaavand, Julia K. Demtröder, Johannes Skraep, Lisbeth Jensen, Peter Breining, Mads Kjølby, Mikkel Holm Vendelbo, Søren E. Degn, Martin K. Thomsen
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with chronic liver inflammation being a major risk factor. Tertiary lymphoid structures (TLS) have been associated with improved survival and better response to immune checkpoint inhibitors in several cancers. However, their role in HCC remains unclear, and findings are often contradictory. METHODS: The study investigated the presence and composition of TLSs across multiple liver disease models, including livers containing HCC. TLSs were characterized to identify the essential cellular components for functional lymphoid activity. The functional role of age-associated B cells (ABCs) was further explored by blocking T-bet expression in B cells, thereby preventing their differentiation into ABCs. RESULTS: TLS frequency was increased in livers containing HCC. Characterization confirmed the presence of key immune cell subsets supporting lymphoid function. Blocking T-bet in B cells led to a reduction in ABCs, which resulted in smaller TLS, a specific decrease in hepatic B cells, and reduced tumor lesion size in HCC-bearing mice. CONCLUSIONS: These findings demonstrate that ABCs promote TLS formation and growth, facilitating B-cell recruitment to the liver and supporting HCC progression. Targeting T-bet-dependent ABC differentiation may represent a novel strategy to limit TLS formation and slow HCC progression.