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.
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)
Zhu B., Symonds A.L.J, Martin JE., Kioussis D., Wraith D., Li SL and Wang P. Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and development of lupus like autoimmune disease. Vol. 205, 2295-2307, J Exp. Medicine, 2008.
Suling Li, Tizong Miao, Meera Sebastian,Punamdip Bhullar,Emma Ghaffari,Mengya Liu,Alistair L.J. Symonds,and Ping Wang. The Transcription Factors Egr2 and Egr3 Are Essential for the Control of Inflammation and Antigen-Induced Proliferation of B and T Cells. Immunity 37, 1–12, October 19, 2012.
Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014-22.
Harris, J.E., K. D. Bishop, N. E. Phillips, J. P. Mordes, D. L. Greiner, A. A. Rossini, M. P. Czech. 2004. Early growth response gene-2, a zinc-fi nger transcription factor, is required for full induction of clonal anergy in CD4+ T cells. J. Immunol. 173: 7331 – 7338.
Supervisor: Dr. Suling Li