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Platelet thromboxane limits T cell immunity to cancer metastasis via ARHGEF1

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE281884 | GEO | 2024/12/02

REPOSITORIES: GEO

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Project description:Analysis of DNA from fixed tissues specimens of 58 primary uveal melanomas, with known clinical outcome, to determine gene copy number variations that were associated with survival. Abstract: Uveal melanomas can be stratified into subgroups with high or low risk of metastatic death, according to the presence of gross chromosomal abnormalities. Where a monosomy 3 uveal melanoma is detected, patient survival at three years is reduced to 50%. However, approximately 5% of patients with a disomy 3 tumour ultimately develop metastasis, and a further 5% of monosomy 3 uveal melanoma patients’ exhibit disease-free survival for more than five years. Despite extensive knowledge of the chromosomal abnormalities occurring in uveal melanoma, the genes driving metastasis are not well defined. Gene copy number variations occurring in a well-characterised cohort of 58 formalin-fixed, paraffin-embedded uveal melanoma samples were identified using the Affymetrix SNP 6.0 whole genome microarray. Four genetic sub-groups of primary uveal melanoma were represented in the patient cohort: 1) disomy 3 with long-term survival; 2) metastasizing disomy 3; 3) metastasizing monosomy 3; and 4) monosomy 3 with long-term survival. Cox regression and Kaplan-Meier survival analysis identified three genes that were associated with differences in patient survival. Patients with an amplification of CNKSR3 (6q) or RIPK1 (6p) demonstrated longer survival than those with gene deletions or no copy number change (log rank, p=0.022 and p<0.001, respectively). Conversely, those patients with an amplification of PENK (8q) showed reduced survival (log rank p<0.001). CNKSR3, RIPK1 and PENK are novel candidate metastasis regulatory genes in uveal melanoma. This is the first report of amplification of a specific gene on 6p that is associated with improved uveal melanoma patient survival and suggests that the development of uveal melanomas with a propensity to metastasise may be limited by genes on 6p. 58 samples in total. Ten disomy 3 with long-term survival. Fifteen disomy 3 with metastasising. Seventeen monosomy 3 with long-term survival. Sixteen monosomy 3 metastasising.

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Platelet thromboxane limits T cell immunity to cancer metastasis via ARHGEF1

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