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Egr2 and 3 mediated T cell tolerance in cancer and their impact in immune checkpoint therapy


Biosciences

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Dr S Li Applications accepted all year round Self-Funded PhD Students Only

About the Project

Tumour infiltrated lymphocytes (TILs) contain tumour reactive T cells and have been used as adoptive cell transfer therapy in patients which can mediate cancer regression. However, without in vitro manipulation, TIL T cells are tolerant to tumour. Although it has been reported that PD1, a negative co-stimulatory molecule, could be induced highly in TIL T cells than T cells from peripheral, the intrinsic mechanisms for TIL T cells to resistant to tumour are largely unknown. The aim of the project is to understand the mechanisms of Egr2 and 3 mediated T cell tolerance in tumour immunology. We will analyse the phenotype and function of Egr2 positive T cells in TILs using EG7 tumor model with GFP-Egr2 knockin mice; investigate what effects of Egr2/3 influence anti-tumour responses of T cells using Egr2/3 knockout and Egr2 overexpression transgenic mice; and understand how Egr2 and 3 expressions are regulated under tumour microenvironment, which may provide the potential bio-marks for tumour immune responses, and new strategy for individual immunotherapy of cancer patients.

Experiment work involved:
1. Establish Eg7 tumor model in GFP-Egr2 knockin mice
2. Characterization of Egr2 positive TIL cells using EG7 tumor model with GFP-Egr2 knockin mice.
3. Examine the function of Egr2/3 positive or negative TIL T cells with proliferation assay, cytokine production and cytotoxic function to see the differences of sub-populations of TILs, providing the evidence why the novel immunotherapeutic strategy can be considered.
4. Define what are the role of Egr2 and 3 in regulation of tumour immune responses using Egr2/3 KO (Egr2/3 genes deleted in lymphocytes) and Egr2 Tg mice (Egr2 gene overexpressed in lymphocytes)


Funding Notes

Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding
Recently the UK Government made available the Doctoral Student Loans of up to £25,000 for UK and EU students and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.

References

Suling Li, Tizong Miao, Meera Sebastian, Punamdip Bhullar, Emma Ghaffari, Mengya Liu, Alistair L. J. Symonds, and Ping Wang, Egr-2 and -3 are essential for both the control of inflammatory autoimmune diseases and antigen receptor mediated activation of B and T cells, Immunity,19;37(4):685-96, 2012.
Miao, T., Symonds, A. L., Singh, R., Symonds, J. D., Ogbe, A., Omodho, B., Zhu, B., Li, S., Wang, P. Egr2 and 3 control adaptive immune responses by temporally uncoupling clonal expansion from T cell differentiation. Miao, T., Symonds, A. L., Singh, R., Symonds, J. D., Ogbe, A., Omodho, B., Zhu, B., Li, S., Wang, P. Egr2 and 3 control adaptive immune responses by temporally uncoupling clonal expansion from T cell differentiation. J Exp Med. 2017 Jun 5;214(6):1787-1808. doi: 10.1084/jem.20160553. Epub 2017 May 9.


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