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Molecular and cellular consequences of tumour-autonomous IL-6 signalling in intrahepatic cholangiocarcinoma

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  • March 7, 2026
  • Jesper B Andersen, et al., University of Copenhagen
Topic/Product:
Immunology, Inflammation Panel 250, Oncology
Disease Area:
Influenza
Sample Type:
Cell Culture Supernatant

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-6high 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-6high 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.

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Authors & Affiliations

Virag Gehl¹, Colm J. O’Rourke¹, Martin Cornillet², Orestis Nousias¹, Achilleas Fardellas³, Supaporn Yangngam¹, Magdalena Rogalska-Taranta¹, Blanca I. Aldana⁴, Dan Hogdall¹˒⁵, Jens U. Marquardt⁶, Niklas K. Björkström², and Jesper B. Andersen¹

¹ Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
² Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden
³ Karolinska Institute, Stockholm, Sweden
⁴ Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
⁵ Oncology, Herlev Hospital, Herlev, Denmark
⁶ Department of Medicine I, University Medical Center Schleswig Holstein Lübeck Campus, Lubeck, Germany

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.