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 immun...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.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFA0807300 and 2021YFA1100600)the National Natural Science Foundation of China(81930085 and 32150710523)the Jiangsu Province International Joint Laboratory for Regenerative Medicine Fund and Suzhou Science and Technology Bureau(ZXL2021440,SWY202202 and SYS2020087).
文摘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.
