PhD Studentships

Prof Martin Bushell, CRUK Scotland Institute & Dr Ed Roberts, CRUK Scotland Institute

Background

CD8⁺ T cells are critical for immune control of cancer; by recognising peptides derived from intracellular proteins presented in the context of MHCI they allow the immune system to surveil the cellular environment and identify threats. In order to counter all possible challenges, both viral and cancer derived, the CD8⁺ T cell repertoire must be hugely diverse. This means that CD8⁺ T cells of a given specificity exist at very low frequencies with an estimate that in humans there are as few as 10 naïve CD8⁺ T cells of each specificity at baseline. In order to counter a threat, however, these T cells must rapidly expand and differentiate to effectors, indeed during an active response T cells are estimated to divide once every 6-8 hours although in some conditions this can be as low as 2-4 hours. Furthermore there is a huge shift in translation moving from quiescent naïve T cells to highly active cytotoxic effector cells. Once a challenge is resolved there is a subsequent huge contraction in numbers with a further shift in phenotype from effector to memory which is less translationally active but remains distinct from naïve cells. During cancer development there is also a further shift within the tumour microenvironment where T cells lose functionality becoming exhausted. Therapies targeting T cell immunity, often based on reinvigorating exhausted T cells, have revolutionized cancer treatment with many cancers previously refractory to treatment now routinely leading to long term survival. There is, however, a pressing need to increase the proportion of patients who benefit from these treatments with many approaches being taken in the field. Despite this, translational control, while central to T cell function, has been neglected in this hunt for new approaches.

To study T cells in cancer there are a range of models available. We have access to OTI T cells which are isolated from a T cell receptor transgenic mouse where all T cells are CD8⁺ T cells specific for the SIINFEKL peptide in the context of H2K^b (an MHCI molecule expressed by C57BL/6 mice). As such large numbers of naïve T cells can be isolated from these mice and these can be expanded in vitro through addition of peptide and cytokine to generate effector T cells or cells with a phenotype approximating T cell memory. Furthermore, these cells can be transferred into mice with tumours expressing SIINFEKL which allows T cells to expand and differentiate under in vivo conditions and to subsequently be re-isolated from different organs including from tumours where, for example, exhausted T cells could be identified.

Research Question

Using ribosome profiling methodologies, we will examine the how translation is controlled in different T cells populations particularly, effector T cells, phenotypes resembling T cell memory and in T cell exhaustion. Importantly we will examine ribosome collisions and co-translation complex assembly of protein complexes and tRNA deployment in these different setting. Ribosome dynamics and ribosome collision sites will be determined and how this intersects with ER targeting mechanisms. These data will be mined bioinformatically, and testable hypothesis identified, and reporter constructs made to examined critical mechanisms arising from these investigations.

Skills/Techniques that will be gained

• Mouse genetic models of cancer

• Immune cells biology

• Cell sorting methods

• Ribosome profiling

• Bioinformatics

To place an application, please visit this site at the CRUK Scotland Institute.

When submitting your application please make sure that you have also completed your application to the Windsor Fellowship and please upload the completed recruitment form.

Duration: 4 years, starting October 2026

Closing Date: 24th November 2025

Interview for this position will take place in January 2026

Lab Websites

Prof Martin Bushell - RNA and Translational Control in Cancer

Dr Ed Roberts - Immune Priming and the Tumour Microenvironment

Relevant Publications