García Sampedro, Andrés; (2024) Deciphering the immuno-oncology crosstalk in primary sclerosing cholangitis and cholangiocarcinoma: role of inflammation and fibrosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background and aims: Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), carrying a high mortality rate. The pathogenesis remains largely unknown; however, it involves inflammation-driven carcinogenesis with significant fibrotic development. Early CCA detection in PSC is key, but current diagnostic approaches are limited. Understanding the intricate interactions between CCA and its fibrotic and inflamed tumour microenvironment (TME) is essential for advancing biomarker discovery. We aim to characterise histological changes preceding CCA development in PSC and identify early detection biomarkers. Additionally, we develop a 3D co-culture model to mimic CCA's fibrotic TME for biomarker validation, enhancing early detection and prognosis. / Methodology: A total of 56 patient tissue sections, including CCA, PSC, and PSC-CCA, were analysed using histology, immunohistochemistry, and spatial transcriptomics (GeoMx platform from Nanostring) to study TME changes. Organotypic 3D co-culture models were established by co-culturing CCA cells with primary hepatic stellate cells (HSCs) and activated T-cells for biomarker discovery and validation. / Results: Histological examination revealed significant bile duct wall changes in PSC and PSC-CCA patients. Spatial transcriptomics, segmenting the tissue into epithelial, immune, and stromal compartments, unveiled altered biological patterns in each compartment, offering novel early detection biomarkers. Our 3D in vitro model of CCA exhibited enhanced growth with ECM addition. Co-culturing CCA cells with HSCs and activated T-cells produced more representative disease models, accurately recapitulating the intricate TME. Proof-of-concept treatment with a p53 reactivator demonstrated the models' potential for testing targeted therapies. / Conclusions: Our findings reveal genetic dysregulation in the TME preceding CCA development in PSC, resulting in a diverse array of cancer and stroma-derived biomarkers with potential for early CCA detection. Leveraging our novel 3D co-culture models, we successfully recapitulate some of these changes in vitro, providing a valuable platform for targeted therapy testing and biomarker validation.

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