PI3K/AKT/mTOR通路
癌症研究
CD8型
蛋白激酶B
下调和上调
T细胞
细胞凋亡
转染
基因敲除
免疫系统
细胞生长
化学
生物
医学
细胞培养
免疫学
生物化学
基因
遗传学
作者
Ying Wang,Chao Zhang,Minjun Yan,Xin Ma,Lairong Song,Bo Wang,Peng Li,Pinan Liu
摘要
Abstract 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.
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