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. Overall design: Whole lungs were harvested from wild-type (WT) and Arhgef1-knockout (KO) littermates 7 days after intravenous injection of B16 melanoma cells for bulk RNA-seq analysis.

转移（Metastasis）是指癌细胞从原发肿瘤扩散至远端器官，是全球90%癌症相关死亡的主要诱因。新近发生转移的癌细胞因缺乏已形成肿瘤的高度免疫抑制微环境，故而对免疫攻击具有独特的易感性。当前学界正致力于利用这一特性，预防存在转移风险的早期癌症患者出现肿瘤复发。本研究证实，环氧合酶（cyclooxygenase, COX）-1抑制剂（包括阿司匹林）可通过解除血小板衍生血栓烷A2（thromboxane A2, TXA2）对T细胞的抑制作用，增强机体抗癌症转移的免疫能力。血小板来源的TXA2可依赖于鸟苷酸交换因子ARHGEF1，在T细胞内触发免疫抑制通路，抑制T细胞受体（T cell receptor, TCR）介导的激酶信号转导、细胞增殖及效应功能。在小鼠体内开展的T细胞特异性条件性敲除Arhgef1实验显示，该操作可增强转移部位的T细胞活化，引发免疫介导的肺与肝转移瘤排斥反应。因此，通过阿司匹林、选择性COX-1抑制剂，或采用血小板特异性敲除COX-1的方式限制TXA2的可用性，可通过依赖T细胞内源性ARHGEF1表达及体内TXA2信号通路的途径，降低癌症转移发生率。本研究揭示了一条全新的免疫抑制通路，该通路可限制T细胞对癌症转移的免疫监视能力，为阿司匹林的抗转移活性提供了机制层面的依据，并为开发更高效的抗转移免疫疗法铺平了道路。整体实验设计：在经尾静脉注射B16黑色素瘤细胞7天后，从野生型（wild-type, WT）及Arhgef1基因敲除（knockout, KO）同窝小鼠体内摘取全肺，用于批量RNA测序（bulk RNA-seq）分析。