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

• 成果类型: Article
• 署名作者: Yang, Jie; Yamashita-Kanemaru, Yumi; Morris, Benjamin I.; Contursi, Annalisa; Trajkovski, Daniel; Xu, Jingru; Patrascan, Ilinca; Benson, Jayme; Evans, Alexander C.; Conti, Alberto G.; Al-Deka, Aws; Dahmani, Layla; Avdic-Belltheus, Adnan; Zhang, Baojie; Okkenhaug, Hanneke; Whiteside, Sarah K.; Imianowski, Charlotte J.; Wesolowski, Alexander J.; Webb, Louise V.; Puccio, Simone; Tacconelli, Stefania; Bruno, Annalisa; Di Berardino, Sara; De Michele, Alessandra; Welch, Heidi C. E.; Yu, I-Shing; Lin, Shu-Wha; Mitra, Suman; Lugli, Enrico; van der Weyden, Louise; Okkenhaug, Klaus; Saeb-Parsy, Kourosh; Patrignani, Paola; Adams, David J.; Roychoudhuri, Rahul
• 署名单位: University of Cambridge; G d'Annunzio University of Chieti-Pescara; G d'Annunzio University of Chieti-Pescara; University of Cambridge; University of Cambridge; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham Institute; Francis Crick Institute; National Taiwan University; National Taiwan University; Universite de Lille; Institut National de la Sante et de la Recherche Medicale (Inserm); CHU Lille; Wellcome Trust Sanger Institute; G d'Annunzio University of Chieti-Pescara
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2662
• DOI: 10.1038/s41586-025-08626-7
• 发表日期: 2025-04-24
• 关键词: low-dose aspirin; p115 rhogef; b-cells; expression; memory; lsc; oncogene; antigen; mouse; cyclooxygenases

摘要

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. 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 A2 (TXA2). TXA2 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 TXA2 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 TXA2 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.