Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally<sup>1,2</sup>. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours<sup>3</sup>. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A<sub>2</sub> (TXA<sub>2</sub>). TXA<sub>2</sub> acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-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 TXA<sub>2</sub> using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA<sub>2</sub> in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

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Publication Details

Journal
Nature
Published
2025-03-05
DOI
https://doi.org/10.1038/s41586-025-08626-7
Citations
75
Primary Topic
Inflammatory mediators and NSAID effects
Type
article
Field-Weighted Citation Impact
104.59

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article

Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity

Charlotte J. Imianowski, Louise van der Weyden, Suman Mitra, Rahul Roychoudhuri et al.
75 citations
Nature
Inflammatory mediators and NSAID effects
104.59
article

Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity

Charlotte J. Imianowski, Louise van der Weyden, Suman Mitra, Rahul Roychoudhuri, Annalisa Bruno, L. Dahmani, Ilinca Patrascan, Shu‐Wha Lin, Jie Yang, Heidi C. E. Welch, Annalisa Contursi, Louise V. Webb, Kourosh Saeb‐Parsy, Enrico Lugli, Benjamin I. Morris, Klaus Okkenhaug, I‐Shing Yu, Stefania Tacconelli, Yumi Yamashita-Kanemaru, Paola Patrignani, Sarah K. Whiteside, Hanneke Okkenhaug, Simone Puccio, Alexander C. Evans, Adnan Avdic-Belltheus, Jayme Benson, Aws Al-Deka, Alexander J. Wesolowski, Sara Di Berardino, Baojie Zhang, David J. Adams, Alberto G. Conti, Jingru Xu, Alessandra De Michele, Daniel Trajkovski
article en
75 citations

Abstract

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally<sup>1,2</sup>. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours<sup>3</sup>. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A<sub>2</sub> (TXA<sub>2</sub>). TXA<sub>2</sub> acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-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 TXA<sub>2</sub> using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA<sub>2</sub> in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

NatureVol. 640(8060)
Centre National de la Recherche Scientifique (FR), Babraham Institute (GB), Inserm (FR), National Taiwan University (TW), Université de Lille (FR), University of Cambridge (GB), The Francis Crick Institute (GB), Wellcome Sanger Institute (GB), University of Chieti-Pescara (IT), Cambridge School (PT), IRCCS Humanitas Research Hospital (IT), NIHR Cambridge Biomedical Research Centre (GB)
Medical Research Council, Biotechnology and Biological Sciences Research Council
Good health and well-being
Openalex Percentile: Top 0%
Inflammatory mediators and NSAID effects
104.59
DOIOpen Access PDFOpenAlex
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