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Analysis of intracellular sCTLA-4 and its contribution to intrinsic cell regulation


Project Description

Cancer immunotherapy is among the most important recent developments in cancer treatment. Despite its impressive successes, however, the response in some patients is often limited and short lived. This is due to factors that hamper the immune response against tumour cells.

The expression of co-inhibitory molecules by tumour cells is a major tumour-mediated immune escape mechanism that leads to the suppression of anti-tumour effector T-cells. Immune checkpoint inhibitors that block the interaction between these co-inhibitory molecules and their receptors have shown remarkable results in enhancing anti-tumour therapeutic efficacy.

Checkpoint inhibitor (CI) antibodies targeting PD-1 and CTLA-4 have been approved for the treatment of different types of cancers. However, current anti-CTLA-4 antibodies can bind the full-length receptor isoform and an alternatively spliced form, called soluble CTLA-4 (sCTLA-4) and recent evidence suggests that the less studied soluble isoform plays a previously unrecognised role in suppressing effector T cells within the tumour environment. A good example of this are studies, which demonstrate that anti-CTLA-4 responsive patients have high serum levels of sCTLA-4, whereas patients with low levels do not.

Our group has developed two selective anti-sCTLA-4 monoclonal antibodies, JMW-3B3 (IgG1λ) and 73-B1 (IgG1), together with recombinant native sCTLA-4, allowing us to dissect the contribution of each CTLA-4 isoform to immune suppression.

In summary, our findings to date have identified sCTLA-4 to contribute to immune suppression of T cell activation, and further, this secretable isoform is actively produced and secreted by some types of cancer including lymphoma, breast and skin cancer. In melanoma, we have also identified a novel mechanism through which tumour cells control serum levels of sCTLA-4 and therefore anti-tumour activity. During our preliminary studies it has become clear that sCTLA-4 has functions, which are not shared with its receptor counterpart. Notably, sCTLA-4 differentially locates to different cellular locations dependent on stimuli received by the cell. Together, our initial data suggest that sCTLA-4 may have a previously unidentified role in maintaining cellular integrity, in addition to its extracellular immunosuppressive role. Antibody therapies targeting CTLA-4 have offered a step forward in the treatment of malignant melanoma and other cancers, but there remains an urgent need to fully understand how this molecule regulates immune cell activity in order to improve current therapeutic regimens and to generate refined, improved therapies.

The aim of this project is to characterise sCTLA-4 cellular localisation in the context of cell activation and differentiation status. Specifically, the student will:

1. Identify and characterise sCTLA-4 expression in immune cell subsets under differential activation states
2. Assess sCTLA-4 cellular localisation by Imagestream flow cytometric analysis in cells at different phases of the cell cycle
3. Identify residues within the unique C terminal region of sCTLA-4, which allows retention in the nucleus
4. Identify any differences in sCTLA-4 localisation in cancer cell lines compared with healthy cells.

These aims, based on our pilot analyses of sCTLA-4 localisation, will provide crucial information on how each CTLA-4 isoform contributes to immune regulation, and for the first time will aim to unify our understanding of both CTLA-4 isoforms in immune cells at different stages of growth and differentiation.
This project provides exceptional opportunities for the student to benefit from diverse expertise and to be exposed to cutting edge techniques including flow cytometry, Imaging flow cytometry, molecular biology, cell-culture, light, electron and confocal microscopy and image analysis techniques.

The student will engage in a novel translational area of research that will contribute to understanding cancer immunology and guiding the development of cancer immunotherapy.

APPLICATION PROCEDURE:
This project is advertised in relation to the research areas of MEDICAL SCIENCES. Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM. Applicants are limited to applying for a maximum of 3 applications for funded projects. Any further applications received will be automatically withdrawn.

Funding Notes

This project is funded by a University of Aberdeen Elphinstone Scholarship. An Elphinstone Scholarship covers the cost of tuition fees only, whether home, EU or overseas.

For details of fees: View Website

Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2:1 Honours degree may be considered provided they have a Distinction at Masters level.

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