Reversing T cell exhaustion through TXA2 pathway inhibition in cancer
Supervisor: Dr Jie Yang
Project Overview
We found that the arachidonic acid metabolite thromboxane A2 (TXA2) acts via ARHGEF1 to limit T cell effector functions. Importantly, ARHGEF1 deletion reduces exhausted T cell populations expressing PD-1, TIM3, TIGIT, TOX, and CD39, while increasing cytokine polyfunctionality. T cell exhaustion is associated with reduced anti-tumour activity, and our data suggest TXA2 signalling drives T cells toward this dysfunctional state. This MSc project will investigate how TXA2 induces T cell exhaustion using in vitro models. The student will establish chronic stimulation systems to model exhaustion, characterise exhaustion marker expression (PD-1, TIM3, TOX, TCF1) by high-dimentional flow cytometry following TXA2 exposure, and assess functional consequences including hierarchical loss of cytokine production and cytotoxicity. We will test whether COX-1 inhibitors like aspirin can prevent or reverse exhaustion phenotypes. The project will employ high-dimensional flow cytometry, functional T cell assays, and co-culture systems with tumour cells. This focused study will determine whether targeting TXA2 signalling could prevent T cell exhaustion, a major barrier to immunotherapy success. Results will inform strategies to maintain T cell fitness in the tumour microenvironment and identify therapeutic windows for intervention with COX-1 inhibitors.
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.
https://www.nature.com/articles/s41577-025-01160-7
3. Wherry, E.J., 2011. T cell exhaustion. Nature immunology, 12(6), pp.492-499.