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

Cellular & Molecular Immunology volume 21, pages 1145–1157 (2024)Cite this article

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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.

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Acknowledgements

This study was 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).

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Authors and Affiliations

  1. The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China

    Jia Zhang, Yuzhu Shi, Xiaotong Xue, Wenqing Bu, Yanan Li, Tingting Yang, Lijuan Cao, Jiankai Fang, Peishan Li, Yongjing Chen, Changshun Shao & Yufang Shi

  2. Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome “Tor Vergata”, Rome, Italy

    Lijuan Cao

  3. Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu, China

    Zhen Li

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Contributions

JZ performed most of the experiments, analyzed the data, and wrote the manuscript. YS and XX produced the mouse models and assisted with the experiments. WB, YL and TY assisted with the experiments. LC, JF, PL, YC and ZL provided reagents and advice. CS and YS supervised the project, designed the experiments, and together edited the manuscript. All authors have read and approved the article. All of the schematic representation are prepared using the BioRender online website (https://www.biorender.com).

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Correspondence to Changshun Shao or Yufang Shi.

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The authors declare no competing interests. YS is editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Zhang, J., Shi, Y., Xue, X. et al. Targeting the glucocorticoid receptor-CCR8 axis mediated bone marrow T cell sequestration enhances infiltration of anti-tumor T cells in intracranial cancers. Cell Mol Immunol 21, 1145–1157 (2024). https://doi.org/10.1038/s41423-024-01202-5

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