Mapping TXA2 signalling networks in T cell immunity
Supervisor: Dr Jie Yang
Project Overview
The immune system can recognise and kill cancer cells but its function is suppressed within tumours preventing rejection of disease. Releasing T cells from immune suppression by targeting immune checkpoints results in effective clinical responses in some patients with cancer. However, only a minority of patients durably respond to existing immunotherapies. Our recent work has discovered a novel inhibitory pathway within T cells that limits T cell function and anti-metastatic immunity (Yang et al., Nature 2025). We found that the arachidonic acid metabolite thromboxane A2 (TXA2) acts via ARHGEF1 to limit T cell effector functions by suppressing kinase signalling. Specifically, TXA2-ARHGEF1 signalling inhibits TCR-driven phosphorylation of PI3K and ERK, critical for T cell activation and proliferation. This MSc project will use CRISPR-Cas9 technology to examine key components of the TXA2-ARHGEF1 pathway. The student will generate knockout T cells using established protocols and characterise their phenotype and function, testing whether these cells show enhanced activation, proliferation, and cytotoxicity against tumour cells. Additionally, the student will map the signalling networks disrupted by TXA2 using phosphoproteomic approaches. The student will treat primary T cells with TXA2 and perform time-course experiments to capture early and late signalling events. Using mass spectrometry-based phosphoproteomics, we will identify phosphorylation changes across key TCR signalling molecules including ZAP70, LAT, ERK, and AKT. The project provides comprehensive training in cutting-edge proteomics, signal transduction analysis, and functional immunology. This mechanistic study will identify precise signalling nodes disrupted by TXA2, revealing potential therapeutic targets beyond COX-1. Results will inform development of novel inhibitors and combination strategies to enhance T cell function in cancer patients.
References
1. Yang, J., Yamashita-Kanemaru, Y., Morris, B.I., Contursi, A., Trajkovski, D., Xu, J., Patrascan, I., Benson, J., Evans, A.C., Conti, A.G. and Al-Deka, A., 2025. Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity. Nature, pp.1-10.
https://www.nature.com/articles/s41586-025-08626-7
2. Bordon, Y., 2025. Aspirin helps T cells to stop cancer spread. Nature Reviews Immunology, pp.1-1.