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

Summary

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.

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

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

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests 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.