Immunovascular microenvironment in relation to prognostic heterogeneity of WNT/β‐catenin‐activated hepatocellular carcinoma

  • Kosuke Matsuda
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Yutaka Kurebayashi
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Yohei Masugi
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Ken Yamazaki
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Akihisa Ueno
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Hanako Tsujikawa
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Hidenori Ojima
    Department of Pathology Keio University School of Medicine Tokyo Japan
  • Minoru Kitago
    Department of Surgery Keio University School of Medicine Tokyo Japan
  • Osamu Itano
    Department of Hepato‐Biliary‐Pancreatic and Gastrointestinal Surgery International University of Health and Welfare School of Medicine Chiba Japan
  • Masahiro Shinoda
    Digestive Diseases Center International University of Health and Welfare Mita Hospital Tokyo Japan
  • Yuta Abe
    Department of Surgery Keio University School of Medicine Tokyo Japan
  • Michiie Sakamoto
    Department of Pathology Keio University School of Medicine Tokyo Japan

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Aim</jats:title><jats:p>WNT/β‐catenin‐activated hepatocellular carcinoma (W/B subclass HCC) is considered a molecularly homogeneous entity and has been linked to resistance to immunotherapy. However, recent studies have indicated possible heterogeneity in the immunovascular microenvironment in this subclass. We set out to test the hypothesis that specific immunovascular features might stratify W/B subclass HCCs into tumors having distinct aggressive natures.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In this study, we analyzed 352 resected HCCs including 78 immunohistochemically defined W/B subclass HCCs. The density of tumor‐infiltrating CD3<jats:sup>+</jats:sup> T cells and the area ratio of vessels encapsulating tumor clusters (VETC) were calculated on tissue specimens. The gene expressions of angiogenic factors were measured by quantitative reverse transcription–polymerase chain reaction. Disease‐free survival (DFS) was assessed using multivariable Cox regression analyses.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The T‐cell density of W/B subclass HCCs was regionally heterogenous within tumor tissues, and focally reduced T‐cell density was observed in areas with VETC. VETC‐positivity (defined as VETC area ratio greater than 1%) was inversely associated with T‐cell infiltration in both W/B subclass and non‐W/B subclass HCCs. Fibroblast growth factor 2 (<jats:italic>FGF2</jats:italic>) gene expression was higher in W/B subclass than in non‐W/B subclass HCCs. The VETC‐positivity and low T‐cell density correlated with increased expression of <jats:italic>FGF2</jats:italic> in W/B subclass HCCs. Additionally, VETC‐positive HCCs showed significantly shorter DFS in W/B subclass HCCs.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In conclusion, the immune and vascular microenvironments are interrelated and are also correlated with clinicopathological heterogeneity in W/B subclass HCC. These results could inform clinical practice and translational research on the development of therapeutic stratification of HCCs.</jats:p></jats:sec>

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