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
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.