Platelet thromboxane limits T cell immunity to cancer metastasis via ARHGEF1
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ABSTRACT:
PROVIDER: PRJNA1186120 | ENA |
REPOSITORIES: ENA
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Project description:Platelet thromboxane limits T cell immunity to cancer metastasis via ARHGEF1
| PRJNA1186122 | ENA
Project description: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.
2024-12-02 | GSE281884 | GEO
Project description: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.
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Project description:Circulating tumor cell clusters/micro-emboli (CTM) possess greater metastatic capacity and survival advantage compared to individual circulating tumor cell (CTCs). However, the formation of CTM subtypes and their role in tumor metastasis remain unclear. In this study, we used a microfluidic Cluster-chip with easy operation and high efficiency to isolate CTM from peripheral blood, which confirmed their correlation with clinicopathological features and identified the critical role of CTC-platelet clusters in BC metastasis. The correlation between platelets and CTM function was further confirmed in a mouse model and RNA-seq of CTM identified high-expressed genes related to hypoxia stimulation and platelet activation which possibly suggested the correlation of hypoxia and CTC-platelet cluster formation. In conclusion, we successfully developed the Cluster-chip platform to realize the clinical capture of CTMs and analyze the biological properties of CTC-platelet clusters, which could benefit the design of potential treatment regimens to prevent CTM-mediated metastasis and tumor malignant progression.
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