Dr Seth Coffelt & Prof Joanne Edwards
The importance of T cells is well established in colorectal cancer, as their abundance in tumours predicts a good outcome in cancer patients. However, for the largest group of colorectal cancers – the microsatellite stable (MSS) group, which represents 80-85% of cases – T cells are largely absent from tumours. Patients with MSS tumours respond poorly to T cell checkpoint inhibitors, such as anti-PD-1. Thus, a greater understanding of how T cells are excluded from MSS tumours is required. Across the genomic landscape of MSS tumours, mutations in WNT/beta-catenin-related genes are the strongest correlative of low T cell infiltration. Thus, the overall goal of this proposal is to mechanistically dissect the interaction between WNT/beta-catenin signalling, immunosurveillance and immune escape in colon cancer. This proposal will specifically focus on intraepithelial lymphocytes (IELs), a group of gut-resident, unconventional T cells consisting of both alpha/beta T cells and gamma/delta T cells, rather than conventional, dendritic cell-educated CD8+ T cells. The Coffelt lab has discovered that IELs recognize and kill pre-cancerous gut epithelial cells. We have found that WNT signalling negatively regulates T cell interacting molecules, but downregulation of these proteins is reversible if WNT signalling is inhibited.
For informal enquiries or further details on the project, please email Dr Seth Coffelt (email@example.com)
For more information on the MRC DTP in Precision Medicine programme: https://www.gla.ac.uk/colleges/mvls/graduateschool/mrcdtpprecisionmedicine/