What controls natural killer cell function in autoimmunity and cancer?

A PhD project for the 2022 doctoral clinical fellows programme with James Lee (primary supervisor, Crick) and Mark Lowdell (UCL)

Project description

Mark Lowdell

Clinical Scientist (Rheumatology), Institute of Immunity and Transplantation, UCL

Natural Killer (NK) cells are innate cytotoxic effector cells that have been implicated in a range of human diseases, but their exact role in these conditions is often poorly understood.

For example, although NK cells are abundantly found in the inflamed intestine in Crohn’s disease and in the CSF in multiple sclerosis, their contribution to the pathogenesis of these conditions remains unclear (1,2). Recent attempts to use NK cells as adoptive cellular therapies in cancer – to exploit their role in tumour immunosurveillance and advantages over T cell-based therapies – have also been limited by unexpectedly weak anti-tumour cytotoxicity without additional activation (3).

A better understanding of the biological pathways that regulate NK cell function, and how these are perturbed in disease and/or could be manipulated for therapeutic benefit, would therefore represent a major advance with wide-ranging implications. 

Our group has optimised methods for CRISPR editing a range of primary immune cells (including T cells, monocytes/macrophages and NK cells) using either Cas9 or Cas12. This has enabled us to identify key genetic regulators of important immunological processes, and determine whether these could targeted therapeutically (4). 

This project will involve performing a genome-wide CRISPR screen to identify genes that regulate NK cell function. This should provide (a) insights into NK cell biology, (b) a basis to uncover how these genes contribute to the pathogenesis of immune-mediated diseases and (c) a series of candidate genes that could be targeted to improve anti-tumour cytotoxicity. Downstream experiments will explore some / all of these possibilities in more detail. 

This project would suit clinicians with an interest in haematological or solid cancers, or autoimmune disease, particularly inflammatory bowel disease or multiple sclerosis. The ideal candidate will have a sound background knowledge of immunology, and some experience in cell culture, lentiviral transduction, and molecular biology. Most importantly, however, we are looking for a bright, enthusiastic, and hard-working individual who has a genuine interest in figuring out immunological mechanisms in human disease (experimental techniques can and will be taught!)

References

  1. de Souza, H.S. and Fiocchi, C. (2016) Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol, 13, 13-27.
  2. Mimpen, M., Smolders, J., Hupperts, R. and Damoiseaux, J. (2020) Natural killer cells in multiple sclerosis: A review. Immunol Lett, 222, 1-11.
  3. Sabry, M. and Lowdell, M.W. (2020) Killers at the crossroads: The use of innate immune cells in adoptive cellular therapy of cancer. Stem Cells Transl Med, 9, 974-984.
  4. Bourges, C., Groff, A.F., Burren, O.S., Gerhardinger, C., Mattioli, K., Hutchinson, A., Hu, T., Anand, T., Epping, M.W., Wallace, C. et al. (2020) Resolving mechanisms of immune-mediated disease in primary CD4 T cells. EMBO Mol Med, 12, e12112.