Platelet thromboxane limits T cell immunity to cancer metastasis via ARHGEF1

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally. Newly metastasising cancer cells are uniquely vulnerable to immune attack, deprived of the highly immunosuppressive microenvironment of established tumours. There is interest in exploiting this vulnerability to prevent recurrence in early cancer patients at risk of metastasis. Here, we show that inhibition of cyclooxygenase (COX)-1, including with aspirin, enhances immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). Platelet TXA2 triggers an immunosuppressive pathway within T cells dependent upon the guanine exchange factor ARHGEF1, suppressing T cell receptor (TCR)-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or through platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner dependent upon T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway limiting T cell immunity to cancer metastasis, providing a mechanistic basis for the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies. FACS-sorted naïve CD8+ T cells from wild-type (WT) and Arhgef1-deficient mice were stimulated with anti-CD3/CD28 antibodies, rhIL-2 and thromboxane A2 analogue U46619 for 5 days, followed by bulk RNA sequencing analysis.