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Combined targeting of PD-L1 and TRAF6 pathways: Implications for Cancer Treatment


   Department of Oncology and Metabolism


About the Project

The majority of deaths from advanced, difficult-to-treat cancers are a result of metastases. Programmed death 1 ligand (PD-L1), a negative regulator of the immune system, is highly expressed in metastatic cancer cells, and its expression is associated with suppressed anti-tumour immunity. Therapeutic antibodies directed at PD-L1 have shown promise in the treatment of various cancers, however only a small proportion of patients respond to these agents. The pro-inflammatory TRAF6/NFκB axis is implicated in metastasis, and previous studies have shown that TRAF6 deletion in mice resulted in T lymphocyte (T-cell) hypersensitivity and spontaneous differentiation. In our laboratories, we have identified a family of novel class of small-molecule inhibitors of TRAF6 that exhibited anti-inflammatory and anti-metastatic properties. Our more recent experiments in T-cells have revealed that the lead TRAF6 inhibitor, when combined with a PD-L1 inhibitor, accelerated and significantly increased cancer cell death. These findings imply that combined targeting of PD-L1 and TRAF6 is of value in restoring anti-tumour immunity.

The aim of the present project is twofold: (a) test the effects of combined pharmacological inhibition and knockdown of TRAF6 and/or PD-L1 on the ability of T-cells to influence the growth of a panel of human and syngeneic cancer cells, and (b) employ an integrative analytic approach that utilizes data from proteomic/genetic/epigenetic analysis to determine the mechanism(s) by which the pro-inflammatory TRAF6/NFKB regulates PD-L1-driven cancer - T-cell interactions.

If successful, the findings of this research will have translational potential in demonstrating that TRAF6 inhibitors - in combination with antibodies directed at PD-L1 - may be of value in restoring the cytotoxic function of tumour antigen-specific T cells, thereby yielding durable response in metastatic cancer. This addresses an unmet need, as both metastasis and poor response to immunotherapy are major clinical problems.

Funding:

Self-funding.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. A relevant MSc is highly desirable.

Enquiries:

Dr Aymen Idris, , 00441142159051

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Oncology & Metabolism' as the department.


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