Tumor-associated high endothelial venules are associated with enhanced lymphocyte infiltration and favorable prognosis in resected hepatocellular carcinoma

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are essential to effective immunotherapy for hepatocellular carcinoma (HCC). Among factors regulating TILs, tumor-associated high endothelial venules (TA-HEVs) have been identified in various cancers and may contribute to TIL recruitment. This study aimed to investigate the clinical significance of TA-HEVs in HCC and their association with TILs. METHODS: 156 patients with HCC who underwent hepatic resection were analyzed. TA-HEVs were identified using double immunohistochemical staining for MECA-79 and CD31. Clinical outcomes and TIL density were compared between TA-HEV-present and -absent cases. Multicolor flow cytometry and RNA sequencing of tumor tissues were also performed. RESULTS: TA-HEVs were observed within tertiary lymphoid structures (TLSs) surrounding tumors in 31 of the 156 cases. The proportion of TLSs containing TA-HEVs increased with TLS maturation. TA-HEV-present cases had significantly better disease-free survival (3 years: 79.8% in TA-HEV-present cases vs 60.1% in TA-HEV-absent cases, p = 0.011). Multivariate analysis identified TA-HEVs as an independent favorable prognostic factor. Moreover, TA-HEV-present cases had significantly higher densities of intra-tumoral CD4⁺ and CD8⁺ T cells. RNA sequencing revealed enhanced pathways related to immune response and lymphocyte activation in TA-HEV-present cases, with high expression of cytotoxic lymphocyte markers. Flow cytometry confirmed elevated proportions of activated CD8⁺ T cells in TA-HEV-present cases. CONCLUSIONS: TA-HEVs in HCC were associated with significantly better prognosis and may contribute to immune activation within the tumor microenvironment.