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

Summary

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’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.

Objectives:

This project will build upon initial findings to:

1. Determine the impact of pharmacological and genetic inhibition of PEPCK2, and the related PEPCK1, on mouse T cell activation, differentiation and effector function

2. Investigate the role of PEPCKs in T cell metabolism

3. Determine how manipulation of PEPCK2 expression might be harnessed to improve the efficacy of anti-tumour T cell responses using in vivo mouse models

References:

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

2. Resistance to TGFb suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22. Brownlie RJ, Garcia C, Ravasz M, Zehn D, Salmond RJ, Zamoyska R. Nat. Commun. 2017, 7:1343

3. mTOR regulation of glycolytic metabolism in T cells. Salmond RJ. Front Cell Dev Biol. 2018, 6:122.

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.

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 minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • 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.