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Immunotherapy: Manipulating T cell metabolism to improve anti-tumour immunity

PGR-P-214

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Mihaela Lorger and Dr Robert Salmond
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

The induction of immune responses to tumours can provide long-lasting protection from cancer. In this regard, T cells can suppress tumour growth by directly killing cancer cells and by producing inflammatory cytokines. Furthermore, advances in immunotherapy have shown the adoptive cell transfer (ACT) of tumour-reactive T cells to be a successful approach to the treatment of cancer. However, in many individuals the T cell response to cancer is ineffective. It has become apparent that the processes of T cell activation and differentiation are linked to the regulation of basic metabolic pathways. These pathways provide energy required for growth, proliferation and effector functions. Dysregulation of cellular metabolism has been linked to the failure of anti-tumour T cell responses. Therefore, a greater understanding of the key pathways and regulators of T cell metabolism has the potential to define new therapeutic targets and approaches to manipulate T cell responses in the clinic. The primary supervisor&rsquo;s research team has determined that a mitochondrial metabolic enzyme, PEPCK2, plays an important role in the differentiation and effector function of inflammatory CD8+ and CD4+ T cells.

<h2 class="heading hide-accessible">Full description</h2>

<h6>Objectives:</h6> <p>This project will build upon initial findings to:</p> <p>1. Determine the impact of pharmacological and genetic inhibition of PEPCK2, and the related PEPCK1, on mouse T cell activation, differentiation and effector function</p> <p>2. Investigate the role of PEPCKs in T cell metabolism</p> <p>3. Determine how manipulation of PEPCK2 expression might be harnessed to improve the efficacy of anti-tumour T cell responses using&nbsp;<em>in vivo&nbsp;</em>mouse models</p> <h6>References:</h6> <p>1. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Salmond RJ, Brownlie RJ, Morrison VL, Zamoyska R. Nat. Immunol. 2014, 15:875-883</p> <p>2. Resistance to TGFb suppression and improved anti-tumor responses in CD8+&nbsp;T cells lacking PTPN22. Brownlie RJ, Garcia C, Ravasz M, Zehn D, Salmond RJ, Zamoyska R. Nat. Commun. 2017, 7:1343</p> <p>3. mTOR regulation of glycolytic metabolism in T cells. Salmond RJ. Front Cell Dev Biol. 2018, 6:122.</p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete an <a href="http://www.leeds.ac.uk/info/130206/applying/91/applying_for_research_degrees">online application form</a> and submit this&nbsp;alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates. Please make it clear in the research information section that you are applying for the International PhD Academy: Medical Research, as well as the title of the project you wish to be considered for.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

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 Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; 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.

<h2 class="heading">Contact details</h2>

<p>Informal enquires reguarding the bespoke taught first year of the PhD programme and research projects can be made by contacting LIMRPhD@leeds.ac.uk.</p> <p>For further information about the application process&nbsp;please contact the Graduate School Office&nbsp;e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>&nbsp;</p>


<h3 class="heading heading--sm">Linked research areas</h3>