About the Project
Interferon-gamma (IFN) is an immune-regulatory cytokine produced by activated T cells. Release of IFN within the TME can trigger the inducible expression of PD-L1 via a defined signalling cascade involving JAK, STAT and IRF1; this in turn suppresses the activity of the tumour-infiltrating T cells, a process termed adaptive resistance. The adaptive upregulation of PD-L1 is known to limit the efficacy of anti-cancer treatments including radiotherapy and immunotherapy. Blockade of IFN signalling may therefore attenuate adaptive resistance, remove the breaks on activated T cells and enhance therapeutic outcome. Many of the molecules involved in IFN signalling are clients of heat shock protein 90 (HSP90), a molecular chaperone that facilitates protein stability, and is constitutively expressed in many solid malignancies. Preliminary data from our lab indicates that inhibition of HSP90 abrogates IFN signalling and prevents adaptive PD-L1 upregulation on numerous murine and human cancer cell lines in vitro.
This project aims to extend these initial observations and use pre-clinical syngeneic murine cancer models to evaluate the potential for HSP90 inhibitors to augment cancer immunity in response to radio- or immunotherapy in vivo. It is hoped that these data will pave the way for early phase clinical trials to evaluate such combinations in cancer patients.
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.
UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the CRUK Manchester Centre PhD Training Scheme (MCRC) website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mcrc-training-scheme/
General enquiries can be directed to [Email Address Removed].
Equality, diversity and inclusion is fundamental to the success of The University of Manchester and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Interview date – 8 January 2021
The duration of this project is four years to commence in October 2021.
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