Combined Radiotherapy and Anti-PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non-Small Cell Lung Cancer
Combined Radiotherapy and Anti-PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non-Small Cell Lung Cancer
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联合放疗与抗PD-L1抗体协同增强非小细胞肺癌的抗肿瘤作用
DOI：
10.1016/j.jtho.2017.04.014
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发表时间：
2017-07-01
影响因子：
20.4
通讯作者：
Zhou, Caicun
中科院分区：
文献类型：
--
作者：
Gong, Xiaomei;Li, Xuefei;Zhou, Caicun
免疫逃逸是肿瘤放疗后抗肿瘤免疫反应的重要因素。程序性死亡1 （PD-1）和程序性死亡配体1 （PD-L1）是导致肿瘤细胞逃避宿主免疫应答的重要免疫检查点分子。本研究旨在探讨PD-L1在NSCLC放射耐药中的作用，以及放疗联合抗PD-L1治疗的抗肿瘤效果。方法：采用小干扰PD-L1 RNA转染、免疫组织化学、Western blot、免疫沉淀等方法，研究磷酸肌苷3-激酶/蛋白激酶B信号转导及转录激活因子3、上皮-间质转化和含有21的三方基序在放疗后PD-L1表达调控中的作用。在小鼠模型中评价放疗与抗pd - l1抗体的协同作用。在一组接受同步放化疗的患者中，对肿瘤标本上的PD-L1表达进行了回顾性研究。结果：常规分级放疗后，PD-L1在体内和体外的表达均有所增加。在小鼠模型中，放疗联合抗pd - l1抗体通过促进cd8阳性T细胞浸润和减少髓源性抑制细胞和肿瘤浸润调节性T细胞的积累，协同增强抗肿瘤免疫。放疗可通过磷酸肌苷3-激酶/AKT及转录信号传导和激活因子等途径上调PD-L1的表达。PD-L1还可能刺激细胞迁移，促进上皮-间质转化过程，从而诱导辐射耐药。下调PD-L1可通过促进细胞凋亡减轻放射耐药。有趣的是，PD-L1表达阴性的患者在放疗后的客观有效率（88%比43.1% [p < 0.001]）和疾病控制率（100%比86.2% [p = 0.026]）均显著高于PD-L1表达阳性的患者。结论：常规分步放疗联合抗pd - l1抗体对非小细胞肺癌具有协同抗肿瘤免疫作用。此外，PD-L1表达可能是非小细胞肺癌放疗治疗反应的重要临床预测因素。(C) 2017年国际肺癌研究协会。Elsevier Inc.出版。版权所有。
Introduction: Immune escape frequently occurs and restricts the durability of the antitumor immune response to radiotherapy. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important immune checkpoint molecules that could cause tumor cells to escape the host immune response. The aim of the study was to explore the role of PD-L1 in radioresistance and the antitumor effect of combined radiotherapy and anti-PD-L1 therapy in NSCLC.Methods: The role of the phosphoinositide 3-kinase/protein kinase B signal transducer and activator of transcription 3, epithelial-mesenchymal transition, and tripartite motif containing 21 in regulating PD-L1 expression after radiotherapy was investigated by small interfering-PD-L1 RNA transfection, immunohistochemistry, Western blot, and immunoprecipitation. The synergistic effect of radiotherapy and anti-PD-L1 antibody was evaluated in a mouse model. PD-L1 expression on tumor specimens was examined in a retrospective cohort of patients who received concurrent chemoradiotherapy.Results: PD-L1 expression was increased in vivo and in vitro after conventionally fractionated radiation. Radiotherapy in combination with anti-PD-L1 antibody synergistically enhanced antitumor immunity by promoting CD8-positive T cell infiltration and reducing the accumulation of myeloid derived suppressor cells and tumor-infiltrating regulatory T cells in a mouse model. Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways. PD-L1 may also stimulate cell migration and facilitate the epithelial-mesenchymal transition process to induce radioresistance. Moreover, down-regulating PD-L1 could alleviate radioresistance' by promoting apoptosis. Intriguingly, patients with negative PD-L1 expression had a significantly higher objective response rate (88% versus 43.1% [p < 0.001]) and disease control rate (100% versus 86.2% [p = 0.026]) than those with positive PD-L1 expression after delivery of radiotherapy.Conclusions: Conventionally fractionated radiotherapy in combination with anti-PD-L1 antibody shows a synergistic antitumor immunity in NSCLC. Furthermore, PD-L1 expression may be a significant clinical predictive factor for treatment response to radiotherapy in NSCLC. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.