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. 2026 Jan 28.
doi: 10.1038/s41698-026-01292-6. Online ahead of print.

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

Lara Heij #  1   2   3   4 , Sikander Hayat #  5   6 , Konrad Reichel #  7   8   9 , Sidrah Maryam  5 , Colm J O'Rourke  10 , Xiuxiang Tan  11 , Marlous van den Braber  8   12 , Jan Verhoeff  8   12   13 , Maurice Halder  5 , Fabian Peisker  5 , Georg Wiltberger  11   14 , Jan Bednarsch  7 , Daniel Heise  7 , Julia Campello Deierl  11 , Sven A Lang  7 , Florian Ulmer  7 , Tom Luedde  15 , Edgar Dahl  16   17 , Danny Jonigk  16   17   18   19 , Jochen Nolting  7 , Shivan Sivakumar  20 , Jens Siveke  21 , Florian Vondran  11 , Flavio G Rocha  22 , Hideo A Baba  23 , Sylvia Hartmann  23 , Jesper B Andersen  10 , Zaynab Hobloss  24 , Ahmed Ghallab  24   25 , Jan G Hengstler  24 , Juan J Garcia Vallejo  8   12 , Rafael Kramann  5 , Ulf Neumann  7   14
Affiliations
Free article

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

Lara Heij et al. NPJ Precis Oncol. .
Free article

Abstract

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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

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