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