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Background <p>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.</p> Methods <p>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.</p> Results <p>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&#xa0;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.</p> Conclusions <p>TA–HEVs in HCC were associated with significantly better prognosis and may contribute to immune activation within the tumor microenvironment.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Shu Aoyama,
  • Takehiro Noda,
  • Hirofumi Akita,
  • Yosuke Mukai,
  • Kazuki Sasaki,
  • Shinichiro Hasegawa,
  • Daisaku Yamada,
  • Yoshito Tomimaru,
  • Tadafumi Asaoka,
  • Hidenori Takahashi,
  • Shogo Kobayashi,
  • Junzo Shimizu,
  • Azumi Ueyama,
  • Takuro Saito,
  • Kansuke Kido,
  • Eiichi Morii,
  • Hisashi Wada,
  • Yuichiro Doki,
  • Hidetoshi Eguchi

摘要

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.