Cancer: Complex 3D modelling of the tumour microenvironment for immunotherapy combination screening


   Faculty of Medicine and Health

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Cancer immunotherapy holds significant promise for the treatment of a range of cancers. Immunotherapies, such Immune checkpoint inhibitors (ICIs) and oncolytic viruses (OVs), have been assessed in clinical trials against a range of solid tumours; however, positive therapeutic responses are often limited due to immune evasion strategies that exist within the tumour. For example, cyclooxygenase (COX2)-mediated production of prostaglandin E2 (PGE2) modulates a range of tumour promoting phenomena including tumour migration and the induction of an immunosuppressive tumour microenvironment. Therefore, intensive research efforts are being made to identify combination therapies that can potentiate the response to immunotherapies. Importantly, our preliminary work has identified eicosapentaenoic acid (EPA) as a promising agent to potentiate both ICI and OVs in solid tumours. Specifically, pre-clinical and clinical evidence has demonstrated that EPA has anti-inflammatory and anti-cancer activity (1-2) and although EPA mechanisms of action are multifactorial, EPA-driven reduction of PGE2 production by COX-2 plays a key role in its anti-cancer activity.

One significant difficulty in the pre-clinical assessment of anti-cancer immunotherapy combinations is that standard in vitro models do not replicate the complexity of the tumour microenvironment, whilst animal models are time consuming, expensive and not always available. Our group has recently developed multi-cellular tumour spheroids (MCTS) in an attempt to model the tumour microenvironment in vitro. The aim of this PhD project is to expand the range, and complexity of MCTS, developing MCTS which incorporate cancer cells, fibroblasts, monocytes, and PBMC for a range tumour types. More complex MCTS will better recapitulate the tumour microenvironment, allowing us to test the anti-cancer activity of immunotherapy-based treatment combinations, and investigate interactions between cancer cells, fibroblasts and immune cells in 3D models. Importantly, during this project MCTS will also be compared with patient samples to validate their relevance as an alternative in vitro cancer model.

The establishment of MCTS will: (i) allow screening for efficacious drug combinations, including EPA with immunotherapies; (ii) enable characterisation of immunosuppressive signalling networks; and (iii) facilitate the identification of potential biomarkers of response. Ultimately this work aims to support the development of novel clinical strategies which will potentiate immunotherapies, including EPA, ICIs and OVs (3).

Techniques associated with this project:

This project will utilise standard cell culture techniques for established cell lines and primary patient samples. The student will grow and treat cells in 3D MCTS, collect conditioned medium to assess soluble mediators by ELISA, and characterise cellular components using immunohistochemistry and flow cytometry. Gene expression analysis will also be performed using real-time RT-PCR. 

This project is part of the International PhD Academy: Medical Research

Eligibility:

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements are:

  • British Council IELTS - score of 7.0 overall, with no element less than 6.5
  • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

How to apply:

Applications can be made at any time. To apply for this project applicants should complete an online application form and attach the following documentation to support their application. 

  • a full academic CV
  • degree certificate and transcripts of marks
  • Evidence that you meet the University's minimum English language requirements (if applicable)

To help us identify that you are applying for this project please ensure you provide the following information on your application form;

  • Select PhD in Medicine, Health and Human Disease as your programme of study
  • Give the full project title and name the supervisors listed in this advert

Any queries regarding the application process should be directed to

Biological Sciences (4)

Funding Notes

This project is aimed at International applicants who are able to self fund their studies or who have a sponsor who will provide their funding.

References

1. Cockbain, A.J., M. Volpato, A.D. Race, A. Munarini, C. Fazio, A. Belluzzi, P.M. Loadman, G.J. Toogood, and M.A. Hull, Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. Gut, 2014. 63(11): p. 1760-8.
2. Volpato, M., S.L. Perry, G. Marston, N. Ingram, A.J. Cockbain, H. Burghel, J. Mann, D. Lowes, E. Wilson, A. Droop, J. Randerson-Moor, P.L. Coletta, and M.A. Hull, Changes in plasma chemokine C-C motif ligand 2 levels during treatment with eicosapentaenoic acid predict outcome in patients undergoing surgery for colorectal cancer liver metastasis. Oncotarget, 2016. 7(19): p. 28139-50.
3. Parrish C, Scott GB, Migneco G, Scott KJ, Steele LP, Ilett E, et al. Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia. Leukemia 2015;29(9):1799-810

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