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

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.

Duration of Project: 36 months/3 years

Clinical Challenge being addressed: Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, features a highly immunosuppressive tumour microenvironment.  This study aims to modulate this immunosuppressive tumour microenvironment to enhance natural killer cell activity.

Laboratory Group

Relevant Reference(s) 

1. Robinson CM, Talty A, Logue SE,  Mnich K,  Gorman AM, Samali A. An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer Cancers (Basel). 2021 Jan; 13(2): 261.
2. Fincham REA, Romana Delvecchio F, Goulart MR,  Yeong JPS, and Kocher HM. Natural killer cells in pancreatic cancer stroma. World J Gastroenterol. 2021 Jun 28; 27(24): 3483–3501.

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.