CD8⁺ T cells are key players in the immune system’s fight against cancer. Our preliminary data show that these cells do infiltrate early metastatic sites in the liver, but their numbers and function decline as the disease progresses. This creates a critical therapeutic window: if we can identify the causes of CD8⁺ T cell failure – and whether this dysfunction is reversible -we may be able to restore their ability to kill tumour cells and improve patient outcomes. However, the phenotype, specificity, and functional status of CD8⁺ T cells in PDAC liver metastases remain poorly understood, making this a timely and important area for research.
This project has three main goals: (1) to define how CD8⁺ T cell activation is coordinated in the liver during PDAC metastasis, (2) to characterise the phenotype, clonality, and activation state of CD8⁺ T cells infiltrating metastases, and (3) to identify the molecular mechanisms that drive their dysfunction.
While immunotherapies have transformed treatment for many cancers, PDAC – especially in metastatic form- remains largely unresponsive. This project addresses a significant gap by investigating whether CD8⁺ T cells are exhausted, under-stimulated, or unable to recognise tumour cells, and by exploring whether their anti-tumour activity can be reawakened.
We will employ advanced techniques such as high-dimensional flow cytometry, multiplex tissue imaging, T cell receptor sequencing, and single-cell RNA sequencing data to map the different states of CD8⁺ T cells. Using mouse models and patient-derived tissues (liver and lymph nodes), we will determine when and where CD8⁺ T cells interact with dendritic cells and how these interactions shape immune responses. Functional assays using a novel tumour model expressing defined antigens will assess CD8⁺ T cell activation, cytotoxicity, and tumour recognition.
The project will be jointly supervised by Professors Michael Schmid, Bob Salmond, and Ainhoa Mielgo. Professors Schmid and Mielgo co-lead the Liverpool Tumour Microenvironment Team and are internationally recognised experts in pancreatic cancer metastasis and tumour immunology. Professor Salmond is a renowned specialist in T cell biology who has pioneered work on the regulatory pathways controlling CD8⁺ T cell effector functions. Together, they provide deep expertise across tumour microenvironment and T cell signalling, supported by strong records of student mentorship and successful publications. You will join a well-funded, collaborative lab environment with access to cutting-edge technologies and regular opportunities for training, presentation, and career development.
By uncovering why T cell-based immunotherapies fail in PDAC liver metastases, this project aims to inform new therapeutic strategies. It is ideal for students interested in immunology, cancer biology, and translational research.
For more information, please visit: http://www.livtme.com
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/