Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
J Thorac Oncol. 2017 Jul;12(7):1085-1097. doi: 10.1016/j.jtho.2017.04.014. Epub 2017 May 3.
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.
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.
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.
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.
免疫逃逸经常发生，限制了抗肿瘤免疫反应对放疗的持久性。程序性死亡 1（PD-1）和程序性死亡配体 1（PD-L1）是重要的免疫检查点分子，可导致肿瘤细胞逃避宿主免疫反应。本研究旨在探讨 PD-L1 在放射抵抗中的作用，以及联合放疗和抗 PD-L1 治疗在非小细胞肺癌（NSCLC）中的抗肿瘤作用。
通过小干扰 PD-L1-RNA 转染、免疫组织化学、Western blot 和免疫沉淀研究了磷酸肌醇 3-激酶/蛋白激酶 B 信号转导子和转录激活子 3、上皮-间充质转化和三结构域包含蛋白 21 在调节放疗后 PD-L1 表达中的作用。在小鼠模型中评估了放疗与抗 PD-L1 抗体的协同作用。在接受同期放化疗的患者的回顾性队列中，检查了肿瘤标本上的 PD-L1 表达。
常规分割放疗后，PD-L1 在体内和体外表达增加。在小鼠模型中，放疗联合抗 PD-L1 抗体通过促进 CD8+T 细胞浸润，减少髓系来源的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。放疗可能通过磷酸肌醇 3-激酶/AKT 和信号转导子和转录激活子 3 途径上调 PD-L1 表达。PD-L1 还可能刺激细胞迁移，促进上皮-间充质转化过程，诱导放射抵抗。此外，下调 PD-L1 可通过促进细胞凋亡来减轻放射抵抗。有趣的是，与 PD-L1 阳性表达的患者相比，PD-L1 阴性表达的患者在接受放疗后具有更高的客观缓解率（88%比 43.1%[p<0.001]）和疾病控制率（100%比 86.2%[p=0.026]）。
常规分割放疗联合抗 PD-L1 抗体在非小细胞肺癌中具有协同抗肿瘤免疫作用。此外，PD-L1 表达可能是 NSCLC 患者对放疗治疗反应的重要临床预测因素。
