循环肿瘤细胞中 PD-L1 的表达在放化疗过程中增加，并预示非小细胞肺癌预后不良。

PD-L1 Expression in Circulating Tumor Cells Increases during Radio(chemo)therapy and Indicates Poor Prognosis in Non-small Cell Lung Cancer.

机构信息

Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.

Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.

出版信息

Sci Rep. 2019 Jan 24;9(1):566. doi: 10.1038/s41598-018-36096-7.

Preclinical studies demonstrated that radiation up-regulates PD-L1 expression in tumor cells, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. However this has not been validated in patients with non-small cell lung cancer due to the difficulty to obtain serial biopsies. Measuring PD-L1 expression in circulating tumor cells (CTCs), may allow real-time monitoring of immune activation in tumor. In this study, whole blood from non-metastatic NSCLC patients was collected before, during, and after radiation or chemoradiation using a microfluidic chip. PD-L1 expression in CTCs was assessed by immunofluorescence and qPCR and monitored through the course of treatment. Overall, PD-L1(+) CTCs were detected in 25 out of 38 samples (69.4%) with an average of 4.5 cells/ml. After initiation of radiation therapy, the proportion of PD-L1(+) CTCs increased significantly (median 0.7% vs. 24.7%, P < 0.01), indicating up-regulation of PD-L1 in tumor cells in response to radiation. In addition, patients positive for PD-L1 (≥5% of CTCs positive for PD-L1) at baseline had shorter PFS. Gene expression analysis revealed that higher levels of PD-L1 were associated with poor prognosis. Therefore, CTCs can be used to monitor dynamic changes of PD-L1 during radiation therapy which is potentially prognostic of response to treatment.

临床前研究表明，辐射会上调肿瘤细胞中 PD-L1 的表达，为 PD-1/PD-L1 抑制剂与辐射联合提供了理论依据。然而，由于难以获得连续的活检，这在非小细胞肺癌患者中尚未得到验证。测量循环肿瘤细胞（CTC）中的 PD-L1 表达，可能允许实时监测肿瘤中的免疫激活。在这项研究中，使用微流控芯片从非转移性 NSCLC 患者的全血中在放疗或放化疗之前、期间和之后采集。通过免疫荧光和 qPCR 评估 CTC 中的 PD-L1 表达，并在治疗过程中进行监测。总的来说，在 38 个样本中的 25 个（69.4%）中检测到 PD-L1(+)CTC，平均每毫升 4.5 个细胞。在开始放疗后，PD-L1(+)CTC 的比例显著增加（中位数 0.7%比 24.7%，P<0.01），表明肿瘤细胞对辐射的 PD-L1 上调。此外，基线时 PD-L1（≥5%的 CTC 阳性）的患者 PFS 更短。基因表达分析显示，PD-L1 水平较高与预后不良相关。因此，CTC 可用于监测放疗期间 PD-L1 的动态变化，这可能与对治疗的反应预后相关。