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<p>Cholangiocarcinoma (CCA) is a deadly cancer, characterized by abundant stroma. The tumor microenvironment (TME) plays an important role in its aggressive behavior and poor response to therapeutics; however, the underlying pathways are unknown. To fill this gap, we used multiplexed immunohistochemistry, high-dimensional cytometry, and single cell transcriptomics. Our findings confirm an abundance of regulatory T cells (Tregs) and a lack of effector memory T cells within the tumor. Tumor-infiltrating T cells show signs of exhaustion. Using our transcriptomic data, we revealed cellular crosstalk in poor prognosis patients. This crosstalk is driven by stromal cells and macrophages. Among the responsible receptor-ligand pairs are GAS6-AXL, VCAN-TLR2, and EGFR-TGF-β. The multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.</p>

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Multimodal single-cell profiling reveals crosstalk between macrophages and stromal cells in poor prognostic cholangiocarcinoma patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月28日

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  • Lara Heij,
  • Sikander Hayat,
  • Konrad Reichel,
  • Sidrah Maryam,
  • Colm J. O’Rourke,
  • Xiuxiang Tan,
  • Marlous van den Braber,
  • Jan Verhoeff,
  • Maurice Halder,
  • Fabian Peisker,
  • Georg Wiltberger,
  • Jan Bednarsch,
  • Daniel Heise,
  • Julia Campello Deierl,
  • Sven A. Lang,
  • Florian Ulmer,
  • Tom Luedde,
  • Edgar Dahl,
  • Danny Jonigk,
  • Jochen Nolting,
  • Shivan Sivakumar,
  • Jens Siveke,
  • Florian Vondran,
  • Flavio G. Rocha,
  • Hideo A. Baba,
  • Sylvia Hartmann,
  • Jesper B. Andersen,
  • Zaynab Hobloss,
  • Ahmed Ghallab,
  • Jan G. Hengstler,
  • Juan J. Garcia Vallejo,
  • Rafael Kramann,
  • Ulf Neumann

摘要

Cholangiocarcinoma (CCA) is a deadly cancer, characterized by abundant stroma. The tumor microenvironment (TME) plays an important role in its aggressive behavior and poor response to therapeutics; however, the underlying pathways are unknown. To fill this gap, we used multiplexed immunohistochemistry, high-dimensional cytometry, and single cell transcriptomics. Our findings confirm an abundance of regulatory T cells (Tregs) and a lack of effector memory T cells within the tumor. Tumor-infiltrating T cells show signs of exhaustion. Using our transcriptomic data, we revealed cellular crosstalk in poor prognosis patients. This crosstalk is driven by stromal cells and macrophages. Among the responsible receptor-ligand pairs are GAS6-AXL, VCAN-TLR2, and EGFR-TGF-β. The multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.