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

Ying Qi; Lang Hu; Chunxia Ji; Xinyu Yang; Jiakai Yao; Di Chen; Yu Yao

Neoplasia: An International Journal for Oncology Research (Aug 2024)

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

Ying Qi,
Lang Hu,
Chunxia Ji,
Xinyu Yang,
Jiakai Yao,
Di Chen,
Yu Yao

Affiliations

Ying Qi: 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
Lang Hu: 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
Chunxia Ji: 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
Xinyu Yang: 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
Jiakai Yao: Immunology Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China
Di Chen: 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; Corresponding authors.
Yu Yao: 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; Corresponding authors.

Journal volume & issue: Vol. 54
p. 101007

Abstract

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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.

Published in Neoplasia: An International Journal for Oncology Research

ISSN: 1522-8002 (Print); 1476-5586 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.journals.elsevier.com/neoplasia/

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