Intratumoral Tertiary Lymphoid Structures Characterized by a B Cell–Related Signature Elicit Antitumor Effect through HAPLN3 in Hepatocellular Carcinoma

作者：Qianwen Zeng, Yujun Liu, J. Chen, Qiaoyi Chen, Zebin Chen, L Peng, Zhijuan Li, Kai Lei, Xiaoxuan Lin, Shijia Liu, Ruiyan Xuan, Ruiming Liang, Zhihang Chen, Chuankai Zhang, Changyi Liao, Youmei Kang, Tianhong Su, Shuling Chen, M. Kuang, Junbin Liao, Jianping Guo, Li Tan · 发表于：Cancer Immunology Research · 年份：2026 · DOI：10.1158/2326-6066.cir-25-0758 · 被引用次数：2 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Immune cells in cancer

The existence of intratumoral tertiary lymphoid structures (TLS) has been reported to be correlated with reduced recurrence of hepatocellular carcinoma (HCC). However, the cellular characteristics and driving mechanisms of TLSs in HCC remain largely unknown. In this study, we compared the clinical outcomes of TLSs in HCC using whole-exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing on a cohort of 339 patients with HCC belonging to different TLS groups. Intratumoral TLSs were significantly associated with improved recurrence-free survival in HCC (P = 0.00013), with higher maturity of TLSs correlating with better prognosis (P = 0.00033). A B cell-related seven-gene signature effectively predicted TLS presence (area under the curve = 0.78) and patient prognosis, outperforming previously reported signatures, which were validated in situ by spatial transcriptomic data. Bulk and single-cell transcriptomic analyses revealed that TLS-positive (TLS+) tumors were immunologically active and strongly associated with immunotherapy response signatures. IgG-producing plasma cells, identified as key effector subsets enriched in TLS+ tumors, exhibited clonal expansion, somatic hypermutation, and high-affinity antibody production. Among potential tumor-enriched TLS-associated genes, HAPLN3 was overexpressed in TLS+ HCC and induced high serum antibody titers (P = 0.0032). Spatial transcriptomics and in vivo experiments confirmed that HAPLN3 promotes B-cell activation, leadin...