Davis Group - Therapeutic opportunities emerging from studies of immune checkpoints
- Simon Davis
ABOUT THE RESEARCH
Our focus has been on the cell biology of the T-cell surface. We developed general methods for crystallizing glycoproteins and determined the structures of key T-cell surface proteins including the first adhesion protein (CD2) and its ligand CD58, the costimulatory receptor CD28 and its ligand CD80, the large tyrosine phosphatase CD45, and most recently a ligand-bound T-cell receptor (TCR; Sušac et al. Cell 2022 185, 3201-3213). We also worked out how weak, specific recognition is achieved by these types of proteins and obtained the first insights into the overall composition of the T-cell surface. Most importantly we proposed, with PA van der Merwe, one of the most complete and best-supported explanations for leukocyte receptor triggering, called the kinetic-segregation (KS) model (youtube.com/watch?v=HygSTSlycok).
A dark secret at the heart of Immunology is that we don’t properly understand how immune responses start,i.e., how the TCR is “triggered” by binding to peptide/MHC. The KS model proposes that TCR phosphorylation is maintained by an equilibrium between kinases and large phosphatases, such as CD45, that’s disturbed locally in favour of kinases when TCRs engage their small ligands, owing to the exclusion of the phosphatases from regions of contact. Using fluorescence and super-resolution microscopy we discovered that, during encounters of T cells with artificial and model cell membranes, sub-μm “close contacts” do indeed form that exclude CD45 and trap smaller molecules including the TCR. What we now want to understand is what happens inside these close contacts. And even more, what we’d like to know is what happens if/when T-cells form close-contacts with antigen-presenting cells, which is going to require very sophisticated, super-resolution fluorescence imaging. To do this we work closely with Prof Sir David Klenerman FRS and Professor Steven Lee, who are experts in single-molecule and super-resolution imaging (both of Cambridge University).
Alongside these basic-science experiments, we’re trying to use our insights into receptor signaling to develop new immunotherapies. It’s well known that lymphocytes are populated by a large variety of inhibitory receptors, commonly referred to as “immune checkpoints”. Remarkably little is known, however, about the signaling pathways used by these receptors or how they are differentiated from one another, constraining their utilization as targets for immunotherapy. One approach to pathway analysis is based on immune-precipitation or “pull-downs”, but important low-affinity interactions may be missed during wash steps. Alternatively, individual domain interactions can be analysed directly, but likely cooperative effects will go unobserved. In unpublished proof-of-concept experiments, we have established a third way, which is to directly visualise the recruitment of fluorescently tagged signaling intermediates to the immune checkpoints, at the time of receptor triggering, using fluorescence imaging. This was made possible by our discovery that T-cell fate decisions are made at large numbers of small ‘microvillar’ contacts formed by T cells with apposing surfaces, that we can visualise on model cell surfaces in a semi hi-throughput fashion using confocal microscopy (Jenkins et al. 2023 Nat Commun 14, 1611. doi: 10.1038). We are planning now to undertake a systematic analysis of three immune checkpoints, PD-1, BTLA and TIGIT, and a fourth, activating receptor, the TCR using the new imaging approach, complemented by arrayed CRISPR screens and the bioinformatic analysis of publicly available genetic (e.g., GWAS) data. In the future, we expect this type of data, extended to all immune checkpoints, to underpin the selection of these receptors as targets for immunotherapy.
A spinout company from this laboratory and that of Professor Richard Cornall (Nuffield Professor of Medicine, Oxford), which is now owned by Gilead Sciences, is presently seeking to create a new class of antibody therapeutics, i.e., the inhibitory superagonists, based on these ideas (see https://www.ox.ac.uk/news/2022-08-04-oxford-spinout-mirobio-acquired-gilead-sciences-405m). The expectation is that this project will involve collaborations with scientists at the Gilead (Oxford) laboratories.
Please see http://davislab-oxford.org/ for more details of our lab’s activities.
Additional supervision may be provided by Dr Mafalda Santos and Dr Sumana Sharma.
Please see the Weatherall Institute for Molecular Medicine (WIMM) for information about applications for a DPhil in Medical Sciences with groups based in the WIMM.
The work in the Davis Laboratory relies on the use of CRISPR and other molecular biology-related techniques to generate and express fluorescently tagged signaling proteins, and to study and characterize the effects of antibodies, and to re-engineer them. Training in cutting edge imaging will be obtained in the laboratories of our principal collaborators, Professor Sir David Klenerman and Professor Steven Lee.
Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.
Paluch C, Santos AM, Anzilotti C, Cornall RJ, Davis SJ. Immune checkpoints as therapeutic targets in autoimmunity. Front Immunol. 2018 9, 2306.
Fernandes RA, Ganzinger KA, Tzou JC, Jönsson P, Lee SF, Palayret M, Santos AM, Carr AR, Ponjavic A, Chang VT, Macleod C, Lagerholm BC, Lindsay AE, Dushek O, Tilevik A, Davis SJ, Klenerman D. (2019) A cell topography-based mechanism for ligand discrimination by the T cell receptor. Proc Natl Acad Sci USA 116, 14002-14010.
Chen KY, Jenkins E, Körbel M, Ponjavic A, Lippert AH, Santos AM, Ashman N, O'Brien-Ball C, McBride J, Klenerman D, Davis SJ Proc Natl Acad Sci USA 2021 118:e2024250118.
Sušac L, Vuong MT, Thomas C, von Bülow S, O'Brien-Ball C, Santos AM, Fernandes RA, Hummer G, Tampé R, Davis SJ. Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC. (2022) Cell 185, 3201-3213.
Jenkins E et al, Lee SF, Davis SJ, Klenerman D. Antigen discrimination by T cells relies on size-constrained microvillar contact. (2023) Nat Commun 14, 1611.