Manipulating cholangiocarcinoma immune-phenotype in a patient derived precision-cut tumour model to improve immune checkpoint inhibition response.

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all annual cancer-related deaths and representing a global health problem. Novel targeted therapies are urgently required to improve the outcome for these patients.

Mouse-models of hepatobiliary cancer are costly, time-consuming and raise ethical concerns. Their ability to replicate human-disease, partially explains high-attrition rates seen upon translation into clinical-trials. Building upon our recent NCRS SKT award we have established a specimen collection network and precision-cut tissue slices (hPCTS) model in Liverpool. These patient-derived 3D-cellular structures can be cultured ex-vivo from normal and tumour tissue enabling us to utilise human-tissue to model human-disease. We propose their implementation to further our understanding of the CCA immune-TME further reducing our reliance on animal models, particularly the xenograft mouse model. immune-checkpoint blockade (ICB) -mediated anti-tumour responses rely on cytotoxic T-cells infiltration to recognize and destroy tumour cells. Immune 'hot' tumours have increased CD8+T-cell infiltration and improved ICB therapy responsiveness. Conversely, immune 'cold' tumours show reduced cytotoxic T-cell infiltration and high proportions of immunosuppressive tumour-associated macrophages and T-regulatory cells. The suboptimal response suggests many CCA tumours have a 'cold' phenotype, comparable to other solid tumours. Combination strategies that modulate tumour immune-phenotype from 'cold' to 'hot' could significantly increase ICB clinical-effectiveness and remains underexplored in CCA.

The overall aim of this project is to evaluate the use of human precision cut tissue slices (hPCTS) generated from resected cholangiocarcinomas (CCA) tumour tissue, as an ex-vivo model to explore strategies to augment the tumour microenvironment and determine response / resistance to immunotherapy and as a platform for novel immunoproteomic biomarker discovery.

The proposed research will be undertaken in the world-renowned Centre for Drug Safety Science at The Department of Pharmacology and Therapeutics, University of Liverpool. The successful applicant will work as part of the liver team alongside other PhD students, post docs, academics and surgeons. They will gain experience in flow cytometry, digital special profiling, immunohistochemistry, slice preparation, ex vivo tissue culture and QRTPCR amongst other techniques.

We welcome applications from highly motivated research students with expertise in pharmacology / biomolecular sciences and a passion for understanding the underlying mechanisms of hepatobiliary disease and improving patient outcomes. A masters in cancer biology and /or immunology would be advantageous.

To apply please send your CV and a letter of application to Dr Laura Randle (Laura.Randle@liverpool.ac.uk)

Funded studentship:

The studentship is funded by National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and is open to UK applicants. The award will pay full tuition fees, bench fees and a UKRI stipend for four years.