Role of Eph tyrosine kinase signalling in T-cell recruitment to cancers

Melanoma is a highly aggressive skin cancer that often metastasizes rapidly. Melanomas have many DNA mutations that change amino acids in proteins. These changes are recognised by T-cells, which then have the potential to kill melanoma cells and hence eliminate the tumour, depending on the balance between cell-killing cytotoxic T-cells and regulatory T-cells that suppress immune responses. Recently developed T-cell based immunotherapies are highly successful in reducing or eliminating melanoma in some patients, but still most patients have little or no response. T-cells enter cancers by crossing endothelial cells lining blood vessels. Eph receptor tyrosine kinases and their Ephrin ligands are expressed by T-cells and endothelial cells, and can promote T-cell attachment to endothelial cells. We hypothesize that Eph/Ephrin pairs increase cytotoxic T-cell recruitment into melanomas by endothelial cells and hence would improve immunotherapy responses. The project aims to determine which Eph/Ephrin pairs are expressed on human endothelial cells and different T-cell subtypes (e.g. cytotoxic, regulatory), and whether they are expressed in T-cells and endothelial cells in melanomas in vivo. It will also test the roles of expressed Ephs/Ephrins in T-cell attachment to endothelial cells and transendothelial migration using in vitro culture models and high-resolution timelapse and confocal microscopy. A 3D system for growing endothelial cells in capillary-like structures will be used to test cytotoxic T-cell recruitment to human melanoma cells. The student will benefit from the complementary skills of Ridley with in vitro models for T-cell/endothelial interaction and Ager with in vivo T-cell homing and melanoma models.
http://www.gw4biomed.ac.uk/doctoral-students/

Keywords:
1 T-cells
2 Cancer
3 Immunotherapy
4 Eph tyrosine kinase
5 Melanoma