Investigation of IRE1a contribution to stromal-natural killer cell crosstalk to enhance natural killer cell mediated pancreatic ductal adenocarcinoma (PDAC) cell death

Aislinn Duggan, Dr. Claire Robinson and Dr. Ashish Neve

Claire Robinson, assistant professor in Physiology at University College Dublin, was awarded with a 5 For The Fight Cancer Immunology Research Fellowship in partnership with Breakthrough Cancer Research.

Imagine a scenario in a tumour where lots of ‘voicemails’ are sent telling the cancer cells and other cell types in the tumour what to do and when to do it. In a tumour ‘voicemails’, known as secreted factors, are continually sent and they often tell cells of the immune system to stop working. This is bad as immune cells should always be on the lookout for cancer cells to destroy them. One example of an immune cell that does this is called a natural killer cell. Natural killer cells, as their name implies, are excellent destroyers of cancer cells, but in a tumor if natural killer cells are told to stop working, then the cancer cells survive.

In pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, there are often a lot of secreted factors in the tumour that stop natural killer cells from working. In this project, we want to find new ways to modulate secreted factors so that they can no longer stop natural killer cells from working. Specifically, we think that if we inhibit a protein called IRE1 in the tumour we can change what gets secreted. This project will use a variety of different approaches to investigate this. We anticipate that the results of this project will inform us on how we can help natural killer cells do their job and kill pancreatic cancer cells.

RESEARCH FINDINGS:

Publications

Robinson CM, Duggan A, Forrester A. ER exit in physiology and disease. Front Mol Biosci. 2024 Jan 18;11:1352970. doi: 10.3389/fmolb.2024.1352970. PMID: 38314136; PMCID: PMC10835805.

Conference Presentations

Title: “Modulating the IRE1α-XBP1s axis in pancreatic ductal adenocarcinoma (PDAC) associated stellate cells: a novel approach to PDAC therapy” presented at:

• EMBO Workshop The endoplasmic reticulum – guardian of cellular homeostasis 2024, Barga, Italy – Presented by Dr. Ashish Neve
• Breakthrough Cancer Research Meet the Cancer Immunotherapy Experts 2024, Dublin, Ireland – Presented by Dr. Claire Robinson, Dr. Ashish Neve and Aislinn Duggan

Irish/American Association of Cancer Research Conference 2024, Dublin, Ireland. Title: “The IRE1-XBP1s pathway is active in pancreatic ductal adenocarcinoma (PDAC) associated stellate cells” – Presented by Aislinn Duggan

Awards

UCD College of Health and Agricultural Science (CHAS) Seed Funding Award  – ‘Illustrating Science’ 2024. Awardee: Ailsinn Duggan