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Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
OBJECTIVE: 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.
摘要：
背景：程序性死亡配体1（PD-L1）表达是一种免疫逃避机制，已在许多肿瘤中得到证实，并且通常与不良预后相关。多年来,抗PD-L1药物作为新型抗癌治疗药物,在众多恶性肿瘤中诱导持久的肿瘤消退,已引起人们的关注.它们可能是2型神经纤维瘤病（NF2）患者的新治疗选择。
目的：本研究的目的是检测NF2相关脑膜瘤中PD-L1的表达，探讨PD-L1下调对肿瘤细胞特性和T细胞功能的影响，并探讨调节PD-L1表达的可能通路，进一步剖析NF2肿瘤免疫抑制的可能机制，为NF2患者提供新的治疗选择。
结果：PD-L1在NF2相关脑膜瘤中异质表达。NF2相关脑膜瘤细胞PD-L1敲低后，肿瘤细胞增殖被显著抑制，细胞凋亡率升高。当T细胞与siPD-L1转染的NF2相关脑膜瘤细胞共培养时，CD69在CD4+和CD8+T细胞上的表达被部分逆转，CD8+T细胞对siPD-L1转染肿瘤细胞的杀伤能力部分恢复。结果还显示PI3K-AKT-mTOR通路调节PD-L1的表达,mTOR抑制剂雷帕霉素快速且持续地抑制PD-L1表达。体内实验结果表明，抗PD-L1抗体可能与mTOR抑制剂在减少肿瘤细胞增殖方面具有协同作用，并且减少的PD-L1表达可能有助于抗肿瘤功效。
结论：靶向PD-L1可能有助于NF2相关脑膜瘤恢复肿瘤浸润淋巴细胞的功能，诱导细胞凋亡，抑制肿瘤增殖。剖析PD-L1驱动的NF2相关脑膜瘤的肿瘤发生的机制将有助于提高我们对肿瘤进展的潜在机制的理解，并有助于进一步完善当前疗法以改善NF2患者的治疗。
目的：本研究的目的是检测NF2相关脑膜瘤中PD-L1的表达，探讨PD-L1下调对肿瘤细胞特性和T细胞功能的影响，并探讨调节PD-L1表达的可能通路，进一步剖析NF2肿瘤免疫抑制的可能机制，为NF2患者提供新的治疗选择。
结果：PD-L1在NF2相关脑膜瘤中异质表达。NF2相关脑膜瘤细胞PD-L1敲低后，肿瘤细胞增殖被显著抑制，细胞凋亡率升高。当T细胞与siPD-L1转染的NF2相关脑膜瘤细胞共培养时，CD69在CD4+和CD8+T细胞上的表达被部分逆转，CD8+T细胞对siPD-L1转染肿瘤细胞的杀伤能力部分恢复。结果还显示PI3K-AKT-mTOR通路调节PD-L1的表达,mTOR抑制剂雷帕霉素快速且持续地抑制PD-L1表达。体内实验结果表明，抗PD-L1抗体可能与mTOR抑制剂在减少肿瘤细胞增殖方面具有协同作用，并且减少的PD-L1表达可能有助于抗肿瘤功效。
结论：靶向PD-L1可能有助于NF2相关脑膜瘤恢复肿瘤浸润淋巴细胞的功能，诱导细胞凋亡，抑制肿瘤增殖。剖析PD-L1驱动的NF2相关脑膜瘤的肿瘤发生的机制将有助于提高我们对肿瘤进展的潜在机制的理解，并有助于进一步完善当前疗法以改善NF2患者的治疗。
