PD-L1 regulates tumor proliferation and T-cell function in NF2-associated meningiomas.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101473265 Publication Model: Print Cited Medium: Internet ISSN: 1755-5949 (Electronic) Linking ISSN: 17555930 NLM ISO Abbreviation: CNS Neurosci Ther Subsets: MEDLINE

Original Publication: Oxford, UK : Wiley-Blackwell, c2008-

Meningioma*/metabolism ; Meningioma*/immunology ; Meningioma*/pathology ; B7-H1 Antigen*/metabolism ; Cell Proliferation*/drug effects ; Cell Proliferation*/physiology ; Meningeal Neoplasms*/metabolism ; Meningeal Neoplasms*/pathology ; Meningeal Neoplasms*/immunology ; T-Lymphocytes*/metabolism ; T-Lymphocytes*/drug effects ; Neurofibromatosis 2*/metabolism; Humans ; Animals ; Mice ; Male ; Female ; Neurofibromin 2/metabolism ; Neurofibromin 2/genetics ; Cell Line, Tumor ; Middle Aged ; Mice, Nude ; Apoptosis/drug effects ; Apoptosis/physiology

Introduction: Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients.
Aims: The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients.
Results: PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4 ⁺ and CD8 ⁺ T cells was partly reversed, and the capacity of CD8 ⁺ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy.
Conclusions: Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.
(© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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82003023 National Natural Science Foundation of China; 82373451 National Natural Science Foundation of China; 81974387 National Natural Science Foundation of China; JYY 2023-2 The Public Welfare Development and the Public Welfare Development and Reform Pilot Project of Beijing Medical Research Institute

Keywords: NF2; PDL1; PI3K/AKT/mTOR; immunosuppression; meningioma

0 (B7-H1 Antigen)
0 (CD274 protein, human)
0 (NF2 protein, human)
0 (Neurofibromin 2)

Date Created: 20240603 Date Completed: 20240603 Latest Revision: 20240708

20240708

PMC11145367

10.1111/cns.14784

38828669