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

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)

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.  See comment in PubMed Commons belowJ Exp Med. 2017 Jun 5;214(6):1787-1808. doi: 10.1084/jem.20160553. Epub 2017 May 9.

 

 

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