Stroma-driven intertumoral and intratumoral heterogeneity of PD-L1 expression in cholangiocarcinoma: Implications for biomarker development and prognostic evaluation

作者：Anna Saborowski, Simon Peters, Jinbo Zhao, Silke Marhenke, Valery Volk, Josephine Sophie Reschke, Anastasiia Korosteleva, Dawei Yi, Tanja Reineke-Plaaß, Jérémy Augustin, Doan Duy Hai Tran, Miguel Ibarra-Arellano, Denis Schapiro, Steffen Lemke, Nicole Krönke, Ilario Giovanni Rapposelli, Oreste Segatto, Melanie Bathon, Christoph Gerdes, Julien Caldéraro, Walter Kolch, Vadim Zhernovkov, Friedrich Feuerhake, Arndt Vogel · 发表于：Hepatology · 年份：2026 · DOI：10.1097/hep.0000000000001686 · 被引用次数：1 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Liver Diseases and Immunity、Cancer Immunotherapy and Biomarkers

BACKGROUND AND AIMS: Immune checkpoint inhibitors are now considered part of the standard of care in biliary tract cancer, based on a statistically significant but overall modest survival benefit in recent pivotal trials. Unlike in other gastrointestinal malignancies, PD-L1-based scores were not significantly associated with survival. Intrahepatic cholangiocarcinomas (iCCA) are morphologically heterogeneous tumors, with a subset of iCCA dominated by stroma-rich areas. We aimed at understanding the potential impact of the intertumoral and intratumoral heterogeneity on PD-L1 expression in iCCA. METHODS: Bulk transcriptome analysis and multiplex immunohistochemistry were performed on 141 clinically annotated resected iCCA. RESULTS: Molecular signatures are critically driven by the relative stroma content, with higher inflammatory gene expression scores in tumor microenvironment (TME)-rich compared with TME-poor tumors. In addition to this intertumoral heterogeneity, we observed a striking intratumoral heterogeneity reflected by an enrichment of PD-L1-expressing cells in stroma-dominant areas. The effect of intratumoral heterogeneity on PD-L1-based scores was confirmed by analyzing "virtual biopsies," that is, randomly selected adjacent tumor regions designed to mimic clinical biopsies, further highlighting the broad challenges associated with biomarker development using needle biopsies. By integrating clinical data, we provide evidence that the prognostic value of PD-L1-expressi...