B7-H4 reduces the infiltration of CD8+T cells and induces their anti-tumor dysfunction in gliomas

被引：1
作者：
Qi, Ying [1 ,2 ,3 ,4 ,5 ]
Hu, Lang [1 ,2 ,3 ,4 ,5 ]
Ji, Chunxia [1 ,2 ,3 ,4 ,5 ]
Yang, Xinyu [1 ,2 ,3 ,4 ,5 ]
Yao, Jiakai [4 ]
Chen, Di [1 ,2 ,3 ,4 ,5 ]
Yao, Yu [1 ,2 ,3 ,4 ,5 ]
机构：
[1] Fudan Univ, Huashan Hosp, Shanghai Med Coll, Dept Neurosurg, Shanghai, Peoples R China
[2] Natl Ctr Neurol Disorders, Shanghai, Peoples R China
[3] Shanghai Key Lab Brain Funct & Restorat & Neural R, Shanghai, Peoples R China
[4] Fudan Univ, Neurosurg Inst, Immunol Lab, Shanghai, Peoples R China
[5] Shanghai Clin Med Ctr Neurosurg, Shanghai, Peoples R China
来源：
NEOPLASIA | 2024年 / 54卷
基金：
中国国家自然科学基金;
关键词：
B7-H4; Glioma; CD8(+)T cell; Tumor infiltrated lymphocytes; Immune dysfunction; CANCER; ACTIVATION; EXHAUSTION; EXPRESSION; SUBSETS;
D O I：
10.1016/j.neo.2024.101007
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
B7-H4 is a promising immune checkpoint molecule in tumor immunotherapy. Our previous study showed that high B7-H4 expression was strongly correlated with deficiency in tumor infiltrated lymphocytes (TILs) in glioma patients. On this basis, we investigated the impact of B7-H4 on CD8+TILs in gliomas and the associated molecular mechanism here. B7-H4-positive tumor samples (n=129) from our glioma cohort were used to assess B7-H4 expression and CD8+TIL quantification by immunohistochemistry. CD8+TILs from five glioma patients cultured with B7-H4 protein were used to evaluate anti-tumor dysfunction by flow cytometry and ELISpot. An orthotopic murine glioma model was used to investigate the role of B7-H4 in glioma CD8+TILs by immunohisto- chemistry and flow cytometry. CD8+TILs from glioma patients cultured with B7-H4 protein were used to explore the potential molecular mechanism by RNA sequencing and western blot. Our results showed that glioma CD8+TIL density was negatively correlated with B7-H4 expression both in glioma patient cohort (P < 0.05) and orthotopic glioma murine model (P < 0.01). B7-H4 also lowered the expression of CD137 and CD103 (P < 0.05 for both) in glioma CD8+TILs and reduced their secretion of the anti-tumor cytokines IFN-gamma and TNF-alpha (P < 0.01 for both) in a dose-dependent manner. Furthermore, B7-H4 was found to induce early dysfunction of glioma CD8+TILs by downregulating the phosphorylation of AKT and eNOS (P < 0.05 for both). In conclusion, B7-H4 reduced the infiltration of glioma CD8+TILs and induced an anti-tumor dysfunction phenotype. B7-H4 may also impair the anti-tumor function of glioma CD8+TILs via the AKT-eNOS pathway. These results indicated that B7-H4 may serve as a potential target in future glioma immunotherapy.
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页数：12
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