Mapping and dissecting molecular mechanisms of thromboxane-mediated immunosuppression in cancer
Primary Supervisor: Dr Jie Yang
Second Supervisor: Professor David Withers
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 such as CTLA-4 and PD-L1 results in strikingly effective clinical responses in some patients with cancer. However, only a minority of patients with a subset of cancers durably respond to existing immunotherapies. There is a need to identify and therapeutically target distinct mechanisms of immunosuppression if we are to build upon early successes in the field of cancer immunotherapy for the benefit of the majority of patients who presently do not respond. 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 have found that the arachidonic acid metabolite thromboxane A2 (TXA2) acts via a Rho guanine exchange factor ARHGEF1 to limit kinase signalling and T cell effector functions. However, the complete molecular mechanisms and broader roles of TXA2 in cancer remain incompletely understood. These mechanistic insights form the basis for research exploring how the TXA2/ARHGEF1 pathway operates at the molecular level to suppress immunity. Fundamental discoveries in this field will provide new targets for the development of therapies aimed at treating individuals with cancer. Research plans: 1. Elucidate the molecular mechanisms by which TXA2/ARHGEF1 suppresses T cell signalling and effector functions in mice and humans. Using proteomic and transcriptional analyses, we will map key signalling networks regulate T cell activation and effector function. 2. Investigate the broader role of TXA2 in cancer beyond immunity. This includes exploring its direct influence on cancer development and investigating cellular sources of immunosuppressive TXA2 in various cancer models. "
Training Opportunities
This project will provide excellent training opportunities for students who are passionate about cancer immunotherapy research. Students will gain expertise in mouse primary and metastatic tumour models, and advanced cellular and molecular immunology techniques including CRISPR-based mutagenesis and genome-wide screening; phosphoproteomics and mass spectrometry. Students will benefit from Oxford's highly collaborative environment with access to both the Department of Oncology and the Centre for Immuno-Oncology (CIO). This unique opportunity provides exceptional exposure to cutting-edge immuno-oncology research spanning fundamental immunology to clinical translation with opportunities for professional development through conference presentations and high-impact publications, preparing them for leadership positions in academic research.
References
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.
Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity | Nature