Abstract：
Brain tumors such as glioblastomas are resistant to immune checkpoint blockade therapy, largely due to limited T cell infiltration in the tumors. Here, we show that mice bearing intracranial tumors exhibit systemic immunosuppression and T cell sequestration in bone marrow, leading to reduced T cell infiltration in brain tumors. Elevated plasma corticosterone drives the T cell sequestration via glucocorticoid receptors in tumor-bearing mice. Immunosuppression mediated by glucocorticoid-induced T cell dynamics and the subsequent tumor growth promotion can be abrogated by adrenalectomy, the administration of glucocorticoid activation inhibitors or glucocorticoid receptor antagonists, and in mice with T cell-specific deletion of glucocorticoid receptor. CCR8 expression in T cells is increased in tumor-bearing mice in a glucocorticoid receptor-dependent manner. Additionally, chemokines CCL1 and CCL8, the ligands for CCR8, are highly expressed in bone marrow immune cells in tumor-bearing mice to recruit T cells. These findings suggested that brain tumor-induced glucocorticoid surge and CCR8 upregulation in T cells lead to T cell sequestration in bone marrow, impairing the anti-tumor immune response. Targeting the glucocorticoid receptor-CCR8 axis may offer a promising immunotherapeutic approach for the treatment of intracranial tumors.
摘要：
脑肿瘤如成胶质细胞瘤对免疫检查点阻断治疗有抗性，主要是由于肿瘤中有限的T细胞浸润。这里,我们显示，小鼠患有颅内肿瘤表现出系统性免疫抑制和T细胞在骨髓隔离，导致脑肿瘤中T细胞浸润减少。在荷瘤小鼠中,升高的血浆皮质酮通过糖皮质激素受体驱动T细胞隔离。由糖皮质激素诱导的T细胞动力学介导的免疫抑制和随后的肿瘤生长促进可以通过肾上腺切除术来消除。糖皮质激素激活抑制剂或糖皮质激素受体拮抗剂的给药，和T细胞特异性糖皮质激素受体缺失的小鼠。T细胞中的CCR8表达在荷瘤小鼠中以糖皮质激素受体依赖性方式增加。此外,趋化因子CCL1和CCL8是CCR8的配体，在荷瘤小鼠的骨髓免疫细胞中高度表达以募集T细胞。这些结果表明，脑肿瘤诱导的糖皮质激素激增和T细胞中的CCR8上调导致骨髓中的T细胞螯合，损害抗肿瘤免疫反应。靶向糖皮质激素受体-CCR8轴可能为颅内肿瘤的治疗提供有希望的免疫治疗方法。
