Overcoming T cell dysfunction to enhance cancer immunotherapy

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. Pertinently, we find that limiting the availability of TXA2 in vivo using aspirin and other COX-1 inhibitors augments anti-metastatic immunity by limiting activation of the ARHGEF1 pathway in T cells. These findings form the basis for research exploring how the TXA2/ARHGEF1 pathway can be exploited to enhance immunity to cancer. Fundamental discoveries in this field will provide new targets for the development of therapies aimed at treating individuals with cancer. Research plans: 1. Investigate the T cell-intrinsic function of the TXA2/ARHGEF1 pathway in modulating anti-tumour immunity and immunotherapy responses. We will examine its synergistic effects with immune checkpoint inhibitors, particularly anti-PD-1 antibodies. 2. Explore how genetic ablation or pharmacological inhibitors targeting the TXA2/ARHGEF1 pathway can augment adoptive T cell immunotherapy. This research will utilise various tumour models and employ single-cell RNA sequencing with TCR-sequencing to dissect polyclonal T cell responses."

Training Oppertunities

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 single-cell RNA-seq, spectral flow cytometry and CRISPR-based mutagenesis. Students will benefit from Oxford's highly collaborative environment with access to both the Department of Oncology and the Center 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