Immunotherapy is revolutionising cancer treatment. For example, antibody-mediated immune checkpoint blockade has become a standard treatment for melanoma and other common cancers. However, not all patients (or cancers) respond to this type of therapy and, at best, only ~50% of patients show response to treatment. To overcome this, new or improved immunotherapy strategies are needed.
We have been investigating how cytotoxic lymphocytes (cytotoxic T cells and natural killer (NK) cells) kill tumour cells and how tumours evade immune attack. Our aim is to identify new strategies for effective immunotherapy. We have found a key role for the enzyme Glycogen Synthase Kinase (GSK)-3 in regulating the activity of cytotoxic lymphocytes. Active GSK-3 blocks lymphocyte activation and we have demonstrated that inhibition of GSK-3 in vivo, using drugs or gene knockouts, enhances cytotoxic activity and boosts tumour rejection. Targeting GSK-3 therefore represents a novel strategy for immunotherapy. However, GSK-3 is expressed in all tissues and many drugs do not target GSK-3 specifically, which has limited their use in the treatment of cancer. This project aims to define the molecular mechanisms by which GSK-3 inhibits cytotoxic lymphocyte activity and to identify other druggable targets within this pathway. We hypothesize that the pathways and molecules downstream of GSK-3 represent alternative drug targets for boosting the activity of cytotoxic lymphocytes and improving immunotherapy.
The project will provide training in molecular and cellular immunology approaches and in informatics-based techniques. The latter will use gene-set enrichment analysis (GSEA), network analysis and statistical methods to analyse transcriptome data from laboratory models and patient cohorts, with the aim of identifying GSK-3 regulated pathways that operate in patient cancers. For laboratory studies, targets of GSK-3 will be analysed in CD8+ T cells and NK cells from human and mouse models using immunological (e.g. tumour killing assays, cytokine release, immune checkpoint expression) and biochemical/genetic methods (enzyme assays, gene and protein expression). These approaches use laboratory techniques such as immune cell purification from blood/tissue, ELISAs and flow cytometry, western blotting, and quantitative RT-PCR. The project is suitable for students with a background in molecular biology, immunology and/or cancer biology with an interest in understanding how the immune system interacts with cancer and how this might be exploited in the development of new immunotherapies. The supervisors have a track record of successful student supervision and collaborative research and are a part of a large, active research programme in cancer immunology.
Links to research groups:
Alison Taylor: https://medicinehealth.leeds.ac.uk/medicine/staff/811/dr-alison-taylor
Robert Salmond: https://medicinehealth.leeds.ac.uk/medicine/staff/733/dr-robert-salmond
Graham Cook: https://medicinehealth.leeds.ac.uk/medicine/staff/239/professor-graham-cook
Jeremie Nsengimana: https://www.ncl.ac.uk/medical-sciences/people/profile/jeremiensengimana.html
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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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