Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.

中文翻译：

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TIMP1 在脑转移中介导星形胶质细胞依赖性局部免疫抑制，作用于浸润性 CD8+ T 细胞。


针对脑转移的免疫疗法在应用于无症状患者时显示出临床益处，但由于未知原因，它们在有症状病例中基本上无效。在这里，我们使用 scRNAseq 剖析了转移相关星形胶质细胞的异质性，并报告了阻断浸润 T 细胞抗肿瘤活性的群体。这种促肿瘤活性是由 pSTAT3+ 星形胶质细胞簇分泌 TIMP1 介导的，TIMP1 作用于 CD63+ CD8+ T 细胞以调节其功能。在小鼠和人类脑转移模型中使用遗传和药理学方法，我们证明将免疫检查点阻断抗体与星形胶质细胞介导的局部免疫抑制的抑制相结合可能有益于有症状的脑转移患者。我们进一步揭示，液体活检中 TIMP1 的存在为选择这种联合免疫疗法的患者提供了生物标志物。总的来说，我们的研究结果表明星形胶质细胞在脑转移中具有意想不到的免疫调节作用，具有临床意义。