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Understanding tumour-mediated suppression of cytotoxic T cell function by rebuilding it in vitro


   School of Cellular and Molecular Medicine

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  Prof C Wuelfing  Applications accepted all year round  Self-Funded PhD Students Only

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 aim to 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 complement a well-established mouse tumour model to investigate tumour immunity in a physiological setting with three-dimensional tissue culture approaches to rebuild key aspects of tumour immunity from defined components. We use imaging approaches to efficiently determine cytotoxic T cell behaviour in the in vitro models. We have already shown that phenotypes of cytotoxic T cells from an in vivo tumour and the tissue culture model are comparable (Ambler et al., 2020). Using our matched experimental system approach, we have generated mechanistic insight into how two elements of tumour-mediated immune suppression, the soluble mediator adenosine and the inhibitory receptor TIM3, function (Edmunds et al., 2021). We now aim to address additional elements of tumour-mediated immune suppression, for example metabolic constraints, fibroblasts, regulatory T cells and therapeutic reagents to engage T cell receptors. Our experimental platform thus allows for the flexible design of Ph.D. projects to investigate mechanisms of tumour-mediated immune suppression.


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)(2021). The adenosine 2A receptor and TIM3directly inhibit the killing of tumor cells by cytotoxic T lymphocytes through interference with cytoskeletal polarization. BioRxiv, doi.org/10.1101/2021.05.20.444944
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