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

Autor:	Qi Y; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China., Hu L; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China., Ji C; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China., Yang X; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China., Yao J; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China., Chen D; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China. Electronic address: dichen18@fudan.edu.cn., Yao Y; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders, Shanghai, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China; Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China. Electronic address: yu_yao@fudan.edu.cn.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2024 Aug; Vol. 54, pp. 101007. Date of Electronic Publication: 2024 May 25.
DOI:	10.1016/j.neo.2024.101007
Abstrakt:	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-γ and TNF-α (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. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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