Bacterial cancer therapy (BCT) is a promising and versatile therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is the most well-studied among bacterial vectors due to advantages in ease of genetic modification, metabolic adaptation, and motility. A longstanding paradox in the field has been the redundancy of T cells for treatment efficacy; instead, STm BCT depends almost exclusively on innate phagocytes for tumour control. Work in our lab is aiming to understand this redundancy of T cell response to BCT, with the aim of improving therapeutic efficacy and translation to the clinic. Using a range of T cell receptor and cytokine reporter mouse models, coupled with an inducible colorectal cancer model we have been able to identify a highly targeted dysregulation of TCR signaling dynamics. Using an in vitro co-culture system we have been able to identify that the dysregulated TCR dynamics are driven by a soluble metabolite. Ongoing work, of which this project will form a large part of, will aim to determine which metabolite(s) are responsible for the dysfunctional T cell response. Using state-of-the-art imaging platforms to detect localisation of metabolites in relation to T cell infiltrates, alongside genetic manipulation of STm and delivery of co-therapies, we aim to reverse T cell dysfunction in this therapy.
Methods used
We will utilise 3D OrbiSIMS (Passerelli etal) imaging mass spectrometry (MS) to visualise the localisation of metabolites within tumours (expertise at University of Nottingham). Localisation of immune infiltrates and STm will be assessed by Vectra Polaris imaging and GeoMX digital spatial profiling (of both transcript and protein) (University of Birmingham). Mouse models of colorectal cancer and in vitro co-cultures of tumour organoids and immune cells are used in the lab. Flow cytometry, ELISAs, RNAseq are other types of analysis that will be used.
Aims
1. Determine the pattern of metabolite changes across the tumour during treatment
2. Compare metabolite distribution to that of infiltrating immune cells.
3. Manipulate T cell responses through engineering STm or delivering co-therapies.
This is a highly multidisciplinary project across University of Birmingham and the University of Nottingham and will draw on key expertise and infrastructure at both Universities. There is significant scope for the project to adapt as the student develops the project and so could suit those with large interest in cancer immunotherapy as much as someone with interested in genetic manipulation of bacteria. If you have an interest in any of the areas stated below, please do contact the lead supervisor to discuss.
Person Specification
Applicants should have a strong background in Immunology or Microbiology, and ideally a background in Metabolism or Cancer. They should have a commitment to research in cancer therapy and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Immunology, Immunotherapy, Cancer, Infection or Metabolism.
How to apply
Informal enquiries should be directed to Kendle Maslowski ([Email Address Removed])
To apply, please download and complete all documentation available at https://more.bham.ac.uk/mrc-aim/phd-opportunities/
AIM DTP
The MRC Advanced Interdisciplinary Models (AIM) Doctoral Training Partnership (DTP) is a multi-institutional DTP between the Universities of Birmingham, Leicester and Nottingham. You will be based at the institution of the first supervisor. More information about the DTP is here
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