PhD studentship: The tumour micro-environment as a determinant of antigen presentation and immune

Dr Matthew Rose-Zerilli; mjrz@soton.ac.uk

Other members of the supervisory team: 

Professor Tim Underwood; T.J.Underwood@soton.ac.uk

Professor Tim Elliott BA PhD; tje@soton.ac.uk

Professor Paul Skipp PhD; P.J.Skipp@soton.ac.uk

Professor Jacek Brodzki; j.brodzki@soton.ac.uk

Duration of the award: 48 months (4 yrs) full time

Project description: 

Advances in cancer immunotherapy have proven that the immune system can be directed to kill cancer cells. Southampton is leading the UK in cancer immunology research based in the our newly built £25M Centre for Cancer Immunology. Current immune checkpoint inhibitors licenced for clinical use fail many patients with only 10-60% of treated patients reaching objective response rates and this is accompanied by high cost and serious side effects in some patients. It is thought that immunotherapy is not effective in all patients because certain cancer cells can hide or produce signals that stop the immune system from attacking the tumour. The same mechanisms are thought to mitigate against the success of anticancer vaccines. Current research to address the reasons for inter-patient variability in response to immunotherapy has focused on tumour immune phenotypes, somatic mutation, the gut microbiome or host genetics. There is new evidence to suggest that the tumour microenvironment (TME) maybe a determinant of antigen presentation and therefore play an important role in the development of anti-tumour immune responses in cancer. We need innovative research to understand more about the role of the TME in tumour antigen presentation and cancer immunosurveillance.

This PhD will focus on oesophageal cancer as this disease type has high levels neoantigen presentation and we have world-leading expertise in this field (whole genome sequencing, single-cell sequencing, organoid modelling and immunopeptidomics).  As yet these data have not been integrated in a coherent manner to answer important clinical questions.  Specifically, this PhD will address the hypothesis that, ‘The tumour microenvironment is a determinant of antigen presentation and immune response in oesophageal cancer'. The main aims of this PhD are to: (1) Link the tumour transcriptome to the immunopeptidome by mathematical modelling of neo-antigen peptide loading to MHC-I molecules. (2) Place antigen presentation into the context of tumour (immune) microenvironment.

The PhD student will acquire data analytic skills, where they will use predictive mathematical modelling to determine the likelihood of selection, and expression level of tumour neoepitopes and components of the antigen processing and presentation pathway, using immunopeptidomic and transcriptomic data from primary human tumour samples. The student will then extend these analyses via further bioinformatical approaches (WGNCA, CIBERSORT & topological data analysis;); focussing on cytokine gene expression signatures, leukocyte infiltration and cancer-associated fibroblasts. These are all factors that determine immunological control of cancer. The student will then investigate the impact of TME/ tumour immunophenotype on the diversity of immunopeptidome presentation by using our novel antigen presentation reporter systems in organoid models. This work will validate the mathematical models developed to predict the level and diversity of peptide presentation.

The student will work in the University priority area of Cancer Immunology at the nexus of three Faculty strategic priorities: cross-Faculty multidisciplinary research, patient proximal research with clear translational potential.

Please contact: Dr Matthew Rose-Zerilli; mjrz@soton.ac.uk; Tel: +44(0)23 81205163

Person Specification

The successful candidate is likely to have the following qualifications:

Funding information 

The project is funded for 4 years and welcomes applicants from the UK and EU who have or expect to obtain at least a first class or upper-second degree in Biological Sciences or allied subjects. Funding will cover fees (£4327 for Academic year 19/20), consumables and a stipend of (£15,009) per annum. Funding is provided by the Wessex Medical Research Charity and The Centre for Cancer Immunology Talent Fund.

Administrative contact and how to apply

Please complete the University's online application form, which you can find at 

https://studentrecords.soton.ac.uk/BNNRPROD/bzsksrch.P_Login?pos=7205&majr=7205&term=201920

You should enter Dr Matthew Rose-Zerilli as your proposed supervisor. To support your application, provide an academic CV (including contact details of two referees), official academic transcripts and a personal statement (outlining your suitability for the studentship, what you hope to achieve from the PhD and your research experience to date). At interview you will be expected to deliver a short presentation (10 mins max) on your background and research experience at the start of the interview.

Informal enquiries relating to the project or candidate suitability should be directed to Dr Matthew Rose-Zerilli (mjrz@soton.ac.uk; Tel: +44(0)23 81205163).