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Re-polarisation of macrophages in the tumour microenvironment of Oesophageal Adenocarcinoma for optimal therapeutic benefit (Ref FHMS - FF - 10 BIO)


   Faculty of Health & Medical Sciences

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  Dr Adam Frampton, Dr N Annels  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Oesophageal cancer – of which adenocarcinoma (OAC) is the predominant type in the UK - is a highly aggressive malignancy, with 5-year survival rates of approximately 15% [1]. Surgically resectable disease is treated with perioperative chemo+/-radiotherapy. Neoadjuvant chemoradiotherapy is known to improve survival, mechanistically this may occur through the induction of an anti-tumour immune response within the tumour microenvironment (TME) [2]. Most immunotherapy trials in OAC have looked at utilising immune checkpoint blockade (ICB), alone or in combination with standard treatments [2]. This project, in collaboration with the Royal Surrey County Hospital (RSCH), is a continuation of our MRC funded PhD which uncovered macrophages as the significant cell population in defining outcomes in OAC. An increase in macrophages that were found to be in close proximity to cytotoxic CD8+ T cells was associated with worse survival, in keeping with an immunosuppressive M2 phenotype. Interrogation of the TCGA-ESCA database has indicated that presence of mast cells within the TME has an impact on survival. Recent work has shown that patients who take antihistamines have improved outcomes from immunotherapy and that this improvement may be due to the relationship between these three cell types [3]. Further work is required to understand the phenotypic and functional characteristics of macrophages and mast cells within the TME of OAC to design novel immunotherapeutic strategies that modulate their interactions to improve patient outcomes. We will use cutting edge techniques to undertake this project with the use of multispectral immunohistochemistry (MSI), 3D tumour modelling with tumour organoids and organotypic slice culture, and in vivo tumour modelling. Our overarching hypothesis is that the release of histamine by intratumoural mast cells polarises macrophages to an immunosuppressive M2 phenotype which impairs the function of critical cytotoxic CD8+ T cells in the TME of OAC. We will use a treatment of an armed oncolytic virus (OV) that has been developed by our laboratory, in combination with antihistamines and anti-PD-1 immunotherapy to repolarise macrophages to their proinflammatory phenotype and induce an anti-tumour response.

Principle Supervisor – Dr Adam Frampton is a Vice-Chancellor's Fellow, Early Career Researcher and Senior Lecturer in Surgical Oncology at The University of Surrey and Consultant General & Hepato-Pancreato-Biliary (HPB) Surgeon at Royal Surrey County Hospital (RSCH). He will provide academic expertise in gastrointestinal cancers and vital links to RSCH for access to patients and tissue. He will ensure the clinical relevance of the project and help with the development of the clinical database, analysis of clinical data and help with scientific professional development through publications, presentations and the establishment of links with collaborators nationally and internationally. Email: [Email Address Removed]

Secondary Supervisor – Dr Nicola Annels has a proven track record in development of basic science and clinical translation in the fields of oncolytic virotherapy and cancer immunotherapy. She is a highly experienced tumour immunologist and has supervised many PhD/MD students in her career to date. Dr Annels has established the multispectral immunohistochemistry imaging, organotypic slice culture and organoid workflows within the laboratory and so has the expertise to assist the successful applicant with all experimental aspects of the project. Dr Annels also has considerable links to industry to help with access to state of the art technologies outside of the University. Email: [Email Address Removed]

Entry requirements

Open to UK and international students with the project starting in October 2023. Note that a maximum of 30% of the studentships will be offered to international students.

You will need to meet the minimum entry requirements for our PhD programme https://www.surrey.ac.uk/postgraduate/biosciences-and-medicine-phd#entry.

How to apply

Applicants are strongly encouraged to contact the relevant principal supervisor(s) to discuss the project(s) before submitting their application.

Applications should be submitted via the [https://www.surrey.ac.uk/postgraduate/biosciences-and-medicine-phd programme page (N.B. Please select the October 2023 start date when applying).

You may opt to apply for a single project or for 2 of these Faculty-funded studentship projects.

When completing your application, in place of a research proposal, please provide a brief motivational document (1 page maximum) which specifies:

  • the reference numbers(s) for the project or two projects you are applying for
  • the project title(s) and principal supervisor name(s)
  • if applying for two projects, please also indicate your order of preference for the projects
  • an explanation of your motivations for wanting to study for a PhD
  • an explanation of your reasons for selecting the project(s) you have chosen

Additionally, to complete a full application, you MUST also email a copy of your CV and 1-page motivational document directly to the relevant project principal supervisor of each project you apply for. Due to short turnaround times for applicant shortlisting, failure to do this may mean that your application is not considered.

Please note that online interviews for shortlisted applicants are expected to take place during the week commencing 30th January.


Funding Notes

Funding is for 3.5 years and includes UKRI-aligned stipend (£17,668 pa for 2022-23), approved University of Surrey fees and a research budget. This studentship is funded by Faculty of Health and Medical Sciences, University of Surrey.

References

1. Pennathur A et al. Oesophageal carcinoma. The Lancet. 2013;381(9864):400-12. 2. Kelly RJ, et al. The Dynamic and Transient Immune Microenvironment in Locally Advanced EAC Post Chemoradiation. Ann Surg. 2018;268(6):992-9. 3. Li H, et al. The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1. Cancer Cell. 2022;40(1):36-52.e9.
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