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(MCRC Non-Clinical) Targeting heat shock protein 90 (HSP90) to overcome adaptive resistance mediated by the PD-L1 immune checkpoint


Faculty of Biology, Medicine and Health

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Dr J Honeychurch , Prof A Choudhury No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The Programmed death ligand 1 (PD-L1) immune checkpoint negatively regulates immune responses to cancer. PD-L1 expressed within the tumour microenvironment (TME) interacts with the PD-1 co-inhibitory receptor present on infiltrating T-cells, leading to their suppression. The presence of PD-L1 within the TME correlates with poor outcome and therapeutic resistance in cancer patients. Strategies targeting the PD-L1/PD-1 axis aim to restore cancer immunity and have shown considerable potential in the clinic, although durable responses are confined to certain patients. Targeting pathways involved in the molecular regulation of PD-L1 may complement existing therapeutic approaches and enhance outcome.

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.

Entry Requirements:
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

Funding Notes

Funding will cover UK tuition fees/stipend only (currently at £19,000 per annum) and running expenses. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable a limited number of full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

The duration of this project is four years to commence in October 2021.
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