Natural killer (NK) cells are a population of lymphocytes with an innate ability to kill infected cells and tumour cells. We combine basic research on the mechanisms of NK cell activation with translational studies aimed at exploiting the anti-tumour activity of these cells and other immune components.
We are investigating the pathways by which NK cells become “armed” with cytotoxic granules (upper panel) containing the killer molecules granzymes and perforin. Both granzymes and perforin are activated by proteolytic cleavage (lower panel) and we are investigating these steps using NK cells derived from patients with rare protease deficiencies. We are studying the pathway of human NK cell development using rare NK cell deficiencies and in vitro differentiation systems.
We are also investigating the interaction between NK cells and different tumour cell types, including myeloma and cervical carcinoma. This research combines analysis of NK receptor interactions with different tumour types, studies of tumour immune evasion and testing of new therapeutic strategies which recruit NK cells in cancer patients. This includes collaborative studies of novel agents in clinical trials.
We are interested in the activation of other immune cells in cancer and have collaborative projects investigating novel “vaccine-based” strategies to boost cellular responses to tumours.
The top panel shows cultured human NK cells transfected with a GFP-granule protein fusion. This enables the labelled cytotoxic granules to be visualised in live cells. These cells are being used to investigate the NK cell killing apparatus and the pathway of degranulation.
The bottom panel shows the proteolytic activation of the NK cell killing machinery. Granzymes are synthesised as inactive zymogens and the pro-domain is removed by cathepsin C. Active granzymes enter the target cell via perforin (which is also proteolytically cleaved). In the target cell, active granzymes cleave caspase molecules and initiate the apoptotic cascade
El-Sherbiny, Y.M, Meade, J.L., Holmes, T.D., McGonagle, D., Mackie, S.L., Morgan, A.W., Cook, G., Feyler, S., Richards, S.J., Davies, F.E., Morgan, G.J. and Cook, G.P. (2007) The requirement for DNAM-1, NKG2D and NKp46 in the NK cell-mediated killing of myeloma cells. Cancer Research 67, 8444-8449.
Bottley, G., Watherston, O.G., Hiew, Y-L., Norrild, B., Cook, G.P. and Blair, G.E. High risk human papillomavirus (HPV) E7 expression reduces cell surface MHC class I molecules and increases susceptibility to NK cells. Oncogene, in press.
Meade, J.L., de Wynter, E.A., Brett, P., Sharif, S.M., Woods, C.G., Markham, A.F. and Cook, G.P. (2006) A family with Papillon-Lefèvre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity. Blood 107:3665-3668.