Dr M Gerlinger
No more applications being accepted
Funded PhD Project (Students Worldwide)
About the Project
BRC Translational Studentships – clinically focussed projects supporting the translational work of the NIHR Biomedical Research Centre at the Royal Marsden and Institute of Cancer Research.
Immunotherapies have revolutionized the treatment of melanomas and lung cancers but they had only modest impact on other common malignancies such as colorectal (CRC) and oesophago-gastric (OGC) cancers. Most CRCs and OGCs have lower mutation loads than the average melanoma or lung cancer and this likely to contribute to the limited activity of single agent checkpoint inhibitors. Additional cancer cell intrinsic factors, such as the activation of oncogenic signalling pathways, the disruption of antigen-presentation pathways or the expression of immune inhibitory cytokines also influence cancer immunogenicity. Overall, it is thought that the balance of pro-immunogenic factors vs. the immune evasion mechanisms that are active in a cancer determine whether a tumour responds to immunotherapy or not.
The identification of immune evasion mechanisms and of therapeutic strategies to reverse these provides the opportunity to increase immunotherapy success in tumours with moderate mutation loads. However, this has been hindered by the lack of immunogenic laboratory models. We have established patient derived CRC and OGC cancer cell cultures and methods for large scale T cell expansion and have combined these into co-culture systems that enable us to study how tumour targeted T cells interact with cancer cells.
The aim of this PhD is to apply genetic perturbations and high throughput transcriptional and genetic analyses to these model systems in order to reveal the immune evasion mechanisms commonly employed by CRCs and OGCs to escape T cell recognition and killing. This will define novel therapeutic targets and inform combination therapies to increase the potency of immunotherapy in these highly prevalent and aggressive cancers.
PROJECT AIMS:
• utilize existing immunogenic CRC and OGC models for the development of a versatile screening platform for CRISPR/CAS9 and cDNA screens
• perform reverse genetic (CRISPR/CAS9- and cDNA-) screens to identify OGC and CRC driver genes that confer resistance to killing by cancer targeted T cells
• mechanistically dissect the identified immune evasion mechanisms using a broad range of bioinformatics, immunological and molecular biology tools and prioritize them for therapeutic targeting
• robustly validate therapeutic approaches to reverse such immune evasion mechanisms in our CRCs and OGC model systems
Candidate profile
Candidates must have a first class or upper second class honours BSc Honours/MSc or equivalent in relevant areas such as cancer biology, immunology or molecular biology
How to apply
Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.
Closing date: Monday 20th November 2017
Applicants should be available for interview 29h and 30th January 2018.
Please apply via the ICR vacancies web portal https://studentapps.icr.ac.uk/
Download a PDF of the complete project proposal:
https://d1ijoxngr27nfi.cloudfront.net/default-document-library/gerlinger-icr-studentship-proposal-form-2016-updated-m-gerlinger-for-web.pdf
Funding Notes
Full funding is available