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About the Project
Summary:
Cytotoxic T cells have the capability of killing tumour target cells. However, this ability is commonly suppressed within the tumour microenvironment. To understand how multiple cell types, soluble mediators and receptors together regulate tumour-mediated immune suppression, we rebuild the tumour microenvironment from defined components in vitro.
Project:
The immune system commonly recognises tumours. Consequently, multiple immune cell types infiltrate many tumour types. However, the ability of tumour-infiltrating immune cells to mount an effective anti-tumour immune response is widely suppressed by the tumour microenvironment. Overcoming such suppression holds great therapeutic promise. However, understanding tumour-mediated immune suppression is a difficult challenge, as many cell types, immune and non-immune, soluble mediators and receptor-ligand couples interact in an integrated, complex system to suppress anti-tumour immunity. To address this challenge, we have rebuilt tumour-mediated suppression of murine and human cytotoxic T cell function in vitro using three-dimensional tissue culture approaches. Combining these approaches with live cell imaging of cytotoxic T cell activation, we have generated mechanistic insight into how three elements of tumour-mediated immune suppression, the soluble mediator adenosine and the inhibitory receptors PD-1 and TIM3, function (Ambler et al., 2020, Edmunds et al., 2022, Alamir et al., 2023). We now address additional elements of tumour-mediated immune suppression, for example metabolic constraints, fibroblasts and therapeutics to engage T cell receptors. Based on extensive initial data (Lu et al., 2023), we are also interested in the vesicular trafficking of the inhibitory receptors PD-1 and TIM3. Our experimental platform thus allows for the flexible design of M.Res. projects to investigate mechanisms of tumour-mediated immune suppression.
MSc by Research
MSc by Research (MSc R) is a 1-year research degree that provides an intensive lab-based training and a preparation for PhD study. You will carry out your studies as part of your research group – like a PhD student does. Towards the end of the year, you write up a thesis on your research and are examined on this. This degree suits students wanting to gain maximum research experience in preparation for PhD applications.
We are keen to recruit a diverse range of students and to ensure our research is open to all. We particularly welcome applications from groups traditionally under-represented in life sciences research. Please check the University webpages for the current tuition fee information. Most MSc R projects also require a bench fee. This varies depending on the research and your project supervisor can tell you the bench fee for the project.
How to apply
Before applying, please read carefully the information on the prospectus Cellular and Molecular Medicine | Study at Bristol | University of Bristol and make sure you have all the documents listed in the Entry Requirements – Admissions Statement and English Language Requirements.
To apply, follow the link Start your application | Study at Bristol | University of Bristol and select the programme “Cellular and Molecular Medicine (PhD)”.
If you have questions about the project, please contact Prof Christoph Wuelfing at Christoph.Wuelfing@bristol.ac.uk
Professor Christoph Wuelfing - Our People (bristol.ac.uk)
If you require assistance with your application, please email fls-pgenquiries@bristol.ac.uk
Funding Notes
This MSc R project is available to UK and international students who wish to self-fund their studies or who have access to their own funding.
References
Ambler, R., Edmunds, G. L., Tan, S. L., Cirillo, S., Pernes, J. I., Ruan, X., Huete-Carrasco, J., Wong, C. C. W., Lu, J., Ward, J., Toti, G., Hedges, A. J., Dovedi, S. J., Murphy, R. F., Morgan, D. J. and Wülfing, C. (DJM and CW are joint last authors)(2020). PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor. Sci. Signal., 13, eaau4518
Edmunds, G. L., Wong, C. C. W., Ambler, R., Milodowski, E., Alamir, H., Cross, S.J., Galea, G., Wülfing, C. and Morgan, D. J. (CW and DJM are joint last authors)(2022). The adenosine 2A receptor and TIM3 directly inhibit the killing of tumor cells by cytotoxic T lymphocytes through interference with cytoskeletal polarization. Commun. Biol., 5, 9
Lu, J., Veler, A., Simonetti, B., Raj, T., Chou, P. H., Cross, S. J., Phillips, A. M., Ruan, X., Huynh, L., Dowsey, A. W., Ye, D., Murphy, R. F., Verkade, P., Cullen, P. J. and Wülfing, C. (2023). Five inhibitory receptors display distinct vesicular distributions in murine T cells. Cells, 12, 2558
Alamir, H., Wong, C.C.W., Alsubaiti, A., Edmunds, G. L., Grant, T., Alsulaimani, S., Boyd, J., Holland, C. J., Morgan, D. J., Gallimore, A. M. and Wülfing, C. (2023) TIM3 is a context-dependent co-regulator of cytotoxic T cell function. BioRxiv https://doi.org/10.1101/2023.08.03.551797
Edmunds, G. L., Wong, C. C. W., Ambler, R., Milodowski, E., Alamir, H., Cross, S.J., Galea, G., Wülfing, C. and Morgan, D. J. (CW and DJM are joint last authors)(2022). The adenosine 2A receptor and TIM3 directly inhibit the killing of tumor cells by cytotoxic T lymphocytes through interference with cytoskeletal polarization. Commun. Biol., 5, 9
Lu, J., Veler, A., Simonetti, B., Raj, T., Chou, P. H., Cross, S. J., Phillips, A. M., Ruan, X., Huynh, L., Dowsey, A. W., Ye, D., Murphy, R. F., Verkade, P., Cullen, P. J. and Wülfing, C. (2023). Five inhibitory receptors display distinct vesicular distributions in murine T cells. Cells, 12, 2558
Alamir, H., Wong, C.C.W., Alsubaiti, A., Edmunds, G. L., Grant, T., Alsulaimani, S., Boyd, J., Holland, C. J., Morgan, D. J., Gallimore, A. M. and Wülfing, C. (2023) TIM3 is a context-dependent co-regulator of cytotoxic T cell function. BioRxiv https://doi.org/10.1101/2023.08.03.551797
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