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Macrophage cell biology studied with super-resolution microscopy


Faculty of Biology, Medicine and Health

About the Project

This new project will be based in Prof. Dan Davis’s laboratory in The University of Manchester, funded by a collaboration with the pharmaceutical company Bristol Myers Squibb, based in the USA. The project will study fundamental aspects of molecular recognition of cancer cells by human macrophages and Natural Killer cells, using super-resolution fluorescence microscopy alongside many molecular and cell biology techniques. We and others have found that immune cell receptors and ligands are organised into micrometer and nanometer-scale domains at cell surfaces. And we have found that the size and composition of these nanoclusters are correlated with immune cell activation and inhibition. For example, the dynamism of receptor nanoclusters can impact signalling by sequestering inhibitory receptors away from activating ones. Alternatively, synergistic signalling can be triggered when discrete receptor nanoclusters coalesce. These emerging features of immune cell surface dynamics represent a paradigm shift in how immune responses can be switched on or off. Of particular relevance here, we have identified that nanoclusters of macrophage activating receptor FcγRI are constitutively associated with nanoclusters of inhibitory receptors. Upon activation, the nanoclusters of activating and inhibitory receptors segregate apart, and this correlates with macrophage activation. In this project we will determine how a novel bispecific antibody produced by Bristol Myers Squibb affects the organisation of cancer cell surfaces to allow better immune recognition by Natural Killer cells and macrophages. Understanding the molecular mechanisms by which immune cells interact with cancer cells will seed new ideas for immune therapies and we strongly believe that a combination of basic research and collaboration with industry is vital. The student will gain a rare set of skills in state-of-the-art microscopy, complex data analysis, molecular and cellular biology techniques, as well as an insight into cancer, inflammation and immunotherapy. See our web-page for an overview: https://www.davislab.manchester.ac.uk/

High level achievement in an undergraduate or a Master’s degree are required in biomedical sciences, immunology, cell biology or any related subject. Some experience in human immune cell biology or microscopy will be useful, but full training will be provided.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. You MUST also submit an online application form - choose PhD Immunology.


Funding Notes

This project is funded by Bristol Myers Squib. Studentship funding is for a duration of 3.5 years to commence on 1 April 2021 and covers UK tuition fees and a UKRI stipend (£15,285 per annum 20/21). Due to funding restrictions the studentship is only open to UK nationals.
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1. Ambrose A.R., Hazime K.S., Worboys, J.D., Niembro-Vivancoa O., Davis D.M., Synaptic secretion from Human Natural Killer cells is diverse and includes supramolecular attack particles, Proc. Natl. Acad. Sci, 117, 23717-23720, (2020).
2. Kennedy P.R., Barthen C., Pitkeathly W.T.E., Williamson D.J., Cumming J., Stacey K.B., Hilton H.G., Carrington M., Parham P., Davis D.M., Genetic diversity impacts the nanoscale membrane organisation and signalling of Natural Killer cell receptors, Science Signaling, 12, 612, (2019).
3. Srpan K., Ambrose A., Karampatzakis A., Saeed M., Cartwright A.N.R., Guldevall K., Dos Santos Cruz De Matos G., Önfelt B., Davis D.M., Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells, J. Cell Biol, 17, 3267-3283, (2018).
4. Bálint S., Lopes F.B., Davis D.M., A Nanoscale Reorganization of IL-15 Cytokine Receptor is Triggered by NKG2D in a Ligand Dependent Manner, Science Signaling, 11, 525, eaal3606, (2018).
5. Lopes F, Balint S, Valvo S, Felce JH, Hessel E, Dustin ML, Davis DM, Membrane nanoclusters of FcγRI segregate from inhibitory SIRPα upon activation of human macrophages, J. Cell Biol, 216, 1123-1141, (2017).

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