Macrophage polarization and spatial architecture characterize the tumor immune microenvironment and prognosis in hepatoblastoma
Menée à partir notamment de l'analyse par immunofluorescence multiplex de 35 échantillons tumoraux fixés au formaldéhyde et inclus en paraffine après prélèvement sur 25 patients, cette étude examine les caractéristiques architecturales et spatiales du microenvironnement tumoral ainsi que le phénotype des macrophages puis met en évidence la valeur pronostique des macrophages surexprimant pSTAT1 après chimiothérapie et l'intérêt du récepteur endothélial vasculaire CLEVER-1 comme marqueur d'immunosuppression et cible thérapeutique potentielle
Hepatoblastoma, the most common primary pediatric liver malignancy, exhibits resistance to contemporary treatments in a subset of patients. Understanding the tumor immune microenvironment is essential for the development of novel immuno-oncological therapies. Herein, the microenvironment of hepatoblastoma was characterized by mapping the spatial distribution of immune cells, identifying prognostic immune features, assessing chemotherapy-induced alterations, and exploring potential immunotherapeutic targets. Whole-slide multiplex immunofluorescence staining (n = 35) was performed on formalin-fixed, paraffin-embedded hepatoblastoma specimens from 25 patients. Immune cell densities were analyzed in precytotoxic and post-cytotoxic treatment samples. Spatial characteristics were assessed using nearest-neighbor distances and Gcross functions, and differential protein abundance patterns were identified using quantitative proteomics (n = 18). This study revealed a predominantly myeloid-rich microenvironment in hepatoblastoma. Macrophages shifted toward a proinflammatory state following cytotoxic treatment. Proinflammatory phosphorylated STAT1 (pSTAT1)+ macrophages were associated with improved patient survival when retained in proximity to tumor cells after chemotherapy. Down-regulation of extracellular matrix pathways was observed in these pSTAT1-rich samples. Common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER-1), an immunosuppressive marker and potential therapeutic target, was abundantly expressed, particularly in stromal macrophages. This study highlights the significance of macrophage phenotypes in hepatoblastoma and their potential as a therapeutic target. Moreover, the findings underline the prognostic value of pSTAT1+ macrophages and CLEVER-1 as a promising immunotherapy target. Future research should explore combination strategies to exploit chemotherapy-induced shifts in macrophage polarization.
The American Journal of Pathology , article en libre accès, 2026