Targeting the glucocorticoid receptor-CCR8 axis mediated bone marrow T cell sequestration enhances infiltration of anti-tumor T cells in intracranial cancers

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Jia Zhang, Yuzhu Shi, Xiaotong Xue, Wenqing Bu, Yanan Li, Tingting Yang, Lijuan Cao, Jiankai Fang, Peishan Li, Yongjing Chen, Zhen Li, Changshun Shao, Yufang Shi
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引用次数: 0

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.

Abstract Image

Abstract Image

靶向糖皮质激素受体-CCR8轴介导的骨髓T细胞螯合可增强颅内癌中抗肿瘤T细胞的浸润。
胶质母细胞瘤等脑肿瘤对免疫检查点阻断疗法具有抗药性,这主要是由于肿瘤中的 T 细胞浸润有限。在这里,我们发现颅内肿瘤小鼠表现出全身免疫抑制和骨髓中的T细胞封存,导致脑肿瘤中的T细胞浸润减少。血浆中皮质酮的升高通过糖皮质激素受体驱动肿瘤小鼠的T细胞封存。肾上腺切除术、糖皮质激素活化抑制剂或糖皮质激素受体拮抗剂以及T细胞特异性糖皮质激素受体缺失的小鼠均可减轻糖皮质激素诱导的T细胞动力学介导的免疫抑制以及随后的肿瘤生长促进作用。肿瘤小鼠 T 细胞中 CCR8 的表达以糖皮质激素受体依赖的方式增加。此外,CCR8 的配体趋化因子 CCL1 和 CCL8 在肿瘤小鼠骨髓免疫细胞中高表达,以招募 T 细胞。这些研究结果表明,脑肿瘤诱导的糖皮质激素激增和T细胞中CCR8的上调会导致T细胞在骨髓中固着,从而损害抗肿瘤免疫反应。以糖皮质激素受体-CCR8轴为靶点可能为治疗颅内肿瘤提供一种前景广阔的免疫治疗方法。
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来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
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