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

作　　者：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 

机构地区：[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 [2]Department of Experimental Medicine and Biochemical Sciences,TOR,University of Rome“Tor Vergata”,Rome,Italy [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

出　　处：《Cellular & Molecular Immunology》2024年第10期1145-1157,共13页中国免疫学杂志（英文版）

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).

摘　　要：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.

关 键 词：Brain tumors Anti-tumor immunity T cell redistribution Glucocorticoid receptor CCR8 

分 类 号：R392[医药卫生—免疫学]