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Understanding the impact of TP53 abnormalities on the immune tumour microenvironment S&T68

  • School: School of Science and Technology
  • Study mode(s): Full-time / Part-time
  • Starting: 2022
  • Funding: UK student / EU student (non-UK) / International student (non-EU) / Fully-funded

Overview

NTU's Fully-funded PhD Studentship Scheme 2022

Project ID: S&T68

Tumours harbouring abnormalities of the TP53 gene, such as a mutations and deletions, are refractory to standard therapies. Our team has an interest in acute myeloid leukaemia (AML), an aggressive bone marrow malignancy that is diagnosed in around 3,200 people in the UK every year. Only 5 out of 100 individuals aged 65 or older (around 5%) will survive for 5 years or more after their diagnosis. The great majority of TP53 mutations in AML are associated with loss-of-function (LOF) of the mutated protein. However, the impact of TP53 abnormalities on the anti-tumour properties of immune cells has not been investigated yet. This line of research has the potential to transform the field and to lead to intellectual property generation.
We are working with a global team of basic researchers and clinicians from the USA, Germany, and the UK to understand how the TP53 gene affects the amount of immune infiltration in the TME of AML and to analyse the functional profile of key cell types with anti-leukaemia activity, including CD8 T cells and natural killer (NK) cells. The results of these initial studies have been published in high profile biomedical journals, including Science Translational Medicine, Blood and Blood Advances (PMID: 34535017; PMID: 33057635; PMID: 32929488; PMID: 32493790). More detailed information about previous achievements is available as a 20-minute podcast at https://ashpublications.org/thehematologist/article/463586/Does-the-Immune-System-Matter-in-Treatment-for-AML.

This project is highly complementary to research efforts that are being led by members of the supervisory team and aims to:

  1. Evaluate the phenotype and functional orientation of bone marrow-infiltrating immune cells. This will be accomplished through the analysis of a unique collection of primary patient samples harbouring TP53 abnormalities.
  2. Understand how the pharmacological re-activation of TP53 affects the expression of inflammatory genes and proteins. The PGR will have access to state-of-the-art technologies (nCounter, GeoMx DSP, proteomics, bulk / single-cell RNA-sequencing) to interrogate the immune transcriptome and proteome of AML cells with well-characterised TP53 mutations.
  3. Characterise the interplay between TP53, actionable immune checkpoints (PD-L1, Tim-3, CTLA4), STAT1 and other interferon-inducible genes that are known to mediate chemotherapy resistance in solid tumours.
  4. Identify biological pathways that are driven by TP53 abnormalities, including the establishment of immunological senescence. The PGR will develop computational biology and data mining approaches to interrogate public transcriptomic datasets and to validate wet-lab findings.

In summary, the goal of this project is to identify molecular vulnerabilities that can be targeted in the clinic to improve patient outcomes. The pharmacological reactivation of TP53 is currently being pursed in early phase clinical trials both in patients with AML and in individuals with solid tumours.

School strategic research priority

This project aligns with Centre for Health, Ageing and Understanding Disease (CHAUD) with the Cancer Biology, Immunology and Therapeutics and Underpinning Technologies research themes. It also aligns with the Centre for Computer Science and Informatics.

Entry qualifications

For the eligibility criteria, visit our studentship application page.

How to apply

For guidance and to make an application, please visit our studentship application page. The application deadline is Friday 14 January 2022.

Fees and funding

This is part of NTU's 2022 fully-funded PhD Studentship Scheme.

Guidance and support

Download our full applicant guidance notes for more information.

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