{
  "abstract": "Background High serum levels of interleukin 6 (IL-6) predict poor prognosis in intrahepatic cholangiocarcinoma (iCCA), a malignancy that often develops in a chronically inflamed milieu. Here, tumour cells are capable of autonomously producing and engaging autocrine IL-6 signalling, yet the consequences of this remain unknown.Objective This study aims to explore the intracellular and intercellular consequences of sustained, tumour-derived IL-6 signalling.Design We generated CRISPR-activated IL-6 high patient-derived iCCA cell models and characterised them using RNA-sequencing and secretome analysis. Therapeutic vulnerabilities were determined with high-throughput drug screening, while the impact of tumour-conditioned media on the phenotype and function of circulating immune cells was assessed with high-dimensional flow cytometry. Spatial transcriptomic analysis (Visium HD) was performed on 14 resected tumours to quantify tumour-derived IL6 expression, cell type composition and ligand-receptor interactions in the tumour microenvironment.Results Chronic IL-6 signalling drives distinct transcriptional programmes, metabolic vulnerabilities and immunomodulatory effects. IL-6 high tumour cells confer sensitivity to nicotinamide phosphoribosyltransferase inhibition, leading to disrupted mitochondrial fitness and selective IL-6 downregulation. Chronic IL-6 signalling also alters the tumour secretome, which modulates immune cell composition and impairs cellular function, including the suppression of MER proto-oncogene tyrosine kinase-mediated macrophage efferocytosis. Spatial transcriptomic analysis confirms that tumour IL6 expression correlates with myeloid cell depletion, cancer-associated fibroblast (CAF) enrichment and enhanced tumour-CAF communication.Conclusions These findings uncover a multifaceted role for IL-6 in shaping tumour-intrinsic, microenvironmental and macroenvironmental features, revealing novel molecular mechanisms and potential therapeutic vulnerabilities in iCCA.",
  "authors": [
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Virag Gehl"
    },
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Colm J O’Rourke"
    },
    {
      "affiliations": [
        "Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Martin Cornillet"
    },
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Orestis Nousias"
    },
    {
      "affiliations": [
        "Karolinska Institute, Stockholm, Sweden"
      ],
      "name": "Achilleas Fardellas"
    },
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Supaporn Yangngam"
    },
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Magdalena Rogalska-Taranta"
    },
    {
      "affiliations": [
        "Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Blanca I Aldana"
    },
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark",
        "Oncology, Herlev Hospital, Herlev, Denmark"
      ],
      "name": "Dan Hogdall"
    },
    {
      "affiliations": [
        "Department of Medicine I, University Medical Center Schleswig Holstein Lübeck Campus, Lubeck, Germany"
      ],
      "name": "Jens U Marquardt"
    },
    {
      "affiliations": [
        "Karolinska Institute, Stockholm, Sweden"
      ],
      "name": "Niklas K Björkström"
    },
    {
      "affiliations": [
        "Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Jesper B Andersen"
    }
  ],
  "title": "Molecular and cellular consequences of tumour-autonomous IL-6 signalling in intrahepatic cholangiocarcinoma",
  "uid": "62023e4c-386f-534d-9c9f-f5cfcb3fc6d2"
}