Defining the Dendritic Cell Landscape in Human Pancreatic Cancer and Draining Lymph Nodes
Primary Supervisor: Keaton Jones
Second Supervisor: Anita Fallah
Project Overview
Background Pancreatic ductal adenocarcinoma (PDAC) is characterised by a profoundly immunosuppressive microenvironment that contributes to resistance to immunotherapy. Tumour-draining lymph nodes (TDLNs) are central to mounting anti-tumour immune responses, as they provide the site where dendritic cells (DCs) present tumour-derived antigens to T cells. However, accumulating evidence suggests that in PDAC, this process is disrupted, resulting in ineffective T cell priming and tolerance. Understanding how the immune landscape of PDAC lymph nodes differs from that of benign pancreatic conditions is essential for understanding barriers to treatment and identifying potential therapeutic targets. Project Aims This MSc project will investigate the composition and function of dendritic cell subsets in human PDAC compared with benign disease, focusing on TDLNs.
Specific objectives include:
1. Characterising immune cell composition Use multiparameter flow cytometry and imaging mass cytometry to quantify and compare DC subsets (cDC1, cDC2, migDCs) in PDAC and benign TDLNs.
2. Assessing functional status of DCs Measure expression of activation and co-stimulatory molecules (e.g., CD80, CD86, CD40) and immunoregulatory markers (e.g., PD-L1).
3. Ex-vivo lymph node analysis Pancreatic draining lymph nodes from patients undergoing surgery for benign and malignant conditions of the pancreas will be collected. Fresh specimens will be processed immediately. Precision cut (vibratome) slices will be cultured in static or perfusion culture systems for up to to 7 days. Immune adjuncts (e.g. TLR agonists) will be administered to determine whether suppression of the immune access is reversible.
Impact This project will provide new insights into how PDAC alters the immune landscape of TDLNs, with a particular focus on dendritic cells as key orchestrators of anti-tumour immunity. Results could identify mechanisms of immune evasion in pancreatic cancer and inform strategies to restore effective antigen presentation and T cell priming.
References
Hughes, D., Evans, A., Go, S., Eyres, M., Pan, L., Mukherjee, S., Soonawalla, Z., Willenbrock, F. and O’Neill, E., 2024. Development of human pancreatic cancer avatars as a model for dynamic immune landscape profiling and personalized therapy. Science Advances, 10(27), p.eadm9071.
https://www.science.org/doi/full/10.1126/sciadv.adm9071