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.
Overview
- The study investigates the limited T cell infiltration in glioblastomas and its role in resistance to immune checkpoint blockade therapy. The study uses mice bearing intracranial tumors and shows that systemic immunosuppression and T cell sequestration in bone marrow lead to reduced T cell infiltration in brain tumors. The primary objective of the study is to understand the mechanisms underlying T cell sequestration in brain tumors and to identify potential immunotherapeutic targets for the treatment of glioblastomas.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions, including adrenalectomy, glucocorticoid activation inhibitors, glucocorticoid receptor antagonists, and T cell-specific deletion of glucocorticoid receptor. The results show that these interventions can abrogate the immunosuppression mediated by glucocorticoid-induced T cell dynamics and the subsequent tumor growth promotion. The study identifies CCR8 expression in T cells as a key finding, which is increased in tumor-bearing mice in a glucocorticoid receptor-dependent manner. The chemokines CCL1 and CCL8, the ligands for CCR8, are also highly expressed in bone marrow immune cells in tumor-bearing mice to recruit T cells. These findings suggest 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.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice, as they suggest that targeting the glucocorticoid receptor-CCR8 axis may offer a promising immunotherapeutic approach for the treatment of glioblastomas. The study identifies several limitations, including the use of mice as a model system and the need for further validation in human studies. Future research directions could include the development of novel immunotherapeutic agents targeting the glucocorticoid receptor-CCR8 axis, as well as the exploration of other mechanisms underlying T cell sequestration in brain tumors.