Multi-omics Dissection of the Immunosuppressive Microenvironment in Pancreatic Cancer
Primary Supervisor: Dr Peter Wan
Second Supervisor: Professor Kerry Fisher
Project Overview
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with limited therapeutic options and poor survival outcomes. Two main molecular subtypes have been defined: classical, characterised by epithelial differentiation and relatively better prognosis, and basal-like, which is more aggressive and therapy resistant. The basal-like subtype is particularly associated with immune exclusion, stromal remodelling, and profound immunosuppression within the tumour microenvironment. Understanding the cellular interactions and signalling networks that drive this hostile environment is critical for developing more effective therapies. The project will begin with generating and integrating multi-omics datasets, including single-cell spatial transcriptomics and multiplex imaging to map the tumour microenvironment of basal-like PDAC at high resolution. Particular attention will be given to the role of cancer-associated fibroblasts (CAFs), examining how different CAF subtypes may cooperate to restrict T-cell infiltration and maintain an immunosuppressive milieu. Building on this, the project will investigate how CAF-derived signals reprogramme macrophages towards suppressive phenotypes, and whether other resident stromal and vascular cells, including pancreatic stellate cells, pericytes, and endothelial cells, also contribute to the establishment of an immune-excluded niche. Ultimately, this project will identify key ligand–receptor interactions and signalling pathways that underpin immune exclusion and sustain immunosuppression in basal-like PDAC. To bridge discovery with translation, findings will be validated using a range of patient-derived models. Organoid co-culture systems will be established to recreate tumour–stroma–immune interactions in vitro, enabling direct testing of how specific CAF subtypes, macrophages, or endothelial cells influence T cell activity. Additional models, including ex vivo tissue slice cultures and patient-derived xenografts, may be employed to capture additional aspects of the tumour microenvironment. Beyond functional validation, the project will explore opportunities to develop or repurpose therapeutic strategies aimed at disrupting the identified immunosuppressive mechanisms. These may then be tested pre-clinically in organoid-based platforms to assess their ability to restore T cell infiltration, reinvigorate anti-tumour immunity, and sensitise basal-like PDAC to existing immunotherapies. In doing so, this research aims to generate both fundamental insight into the biology of PDAC and translational research that may inform the design of future therapeutic strategies.
Training Opportunities
This DPhil will provide comprehensive training at the interface of tumour biology, immunology, and translational cancer research. You will gain hands-on expertise in multi-omics approaches, including spatial transcriptomics and multiplex imaging, to profile the PDAC microenvironment at single-cell resolution. Training will also cover computational modelling to analyse cell–cell communication and infer signalling pathways driving immune exclusion. On the experimental side, you will establish and work with patient-derived models, including organoid–immune co-cultures, ex vivo tissue slice cultures, and xenograft systems, to validate hypotheses in physiologically relevant contexts. You will acquire skills in functional immunology assays to measure T cell activity and in testing candidate therapeutic strategies that target stromal–immune interactions. Close collaboration with clinical and translational teams at Oxford will provide exposure to fresh patient material and the opportunity to connect laboratory discoveries with potential therapeutic applications.
References
Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C., Miller, D.K., Christ, A.N., Bruxner, T.J., Quinn, M.C. and Nourse, C., 2016. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531(7592), pp.47-52.
Elyada, E., Bolisetty, M., Laise, P., Flynn, W.F., Courtois, E.T., Burkhart, R.A., Teinor, J.A., Belleau, P., Biffi, G., Lucito, M.S. and Sivajothi, S., 2019. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer discovery, 9(8), pp.1102-1123.
Genomic analyses identify molecular subtypes of pancreatic cancer | Nature
https://aacrjournals.org/cancerdiscovery/article-abstract/9/8/1102/42174