Bergmann Sonja, Coym Anja, Ott Leonie, Soave Armin, Rink Michael, Janning Melanie, Stoupiec Malgorzata, Coith Cornelia, Peine Sven, von Amsberg Gunhild, Pantel Klaus, Riethdorf Sabine
Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Oncoimmunology. 2020 Mar 23;9(1):1738798. doi: 10.1080/2162402X.2020.1738798. eCollection 2020.
Immune checkpoint inhibition (ICI) of the PD-1/PD-L1 axis shows durable responses in a subset of patients with metastatic urothelial carcinoma (UC). However, PD-L1 expression in tumor biopsies does not necessarily correlate with response to PD-1/PD-L1 inhibitors. Thus, a reliable predictive biomarker is urgently needed. Here, the expression of PD-L1 on circulating tumor cells (CTCs) in blood from patients with advanced UC was analyzed. For this purpose, an assay to test PD-L1 expression on CTCs using the CellSearch® system was established using cells of five UC cell lines spiked into blood samples from healthy donors and applied to a heterogeneous cohort of UC patients. Enumeration of CTCs was performed in blood samples from 49 patients with advanced UC. PD-L1 expression in ≥1 CTC was found in 10 of 16 CTC-positive samples (63%). Both intra- and inter-patient heterogeneity regarding PD-L1 expression of CTCs were observed. Furthermore, vimentin-expressing CTCs were detected in 4 of 15 CTC-positive samples (27%), independently of PD-L1 analysis. Both CTC detection and presence of CTCs with moderate or strong PD-L1 expression correlated with worse overall survival. Analyses during disease course of three individual patients receiving ICI suggest that apart from CTC numbers also PD-L1 expression on CTCs might potentially indicate disease progression. This is the first study demonstrating the feasibility to detect CTC-PD-L1 expression in patients with advanced UC using the CellSearch® system. This assay is readily available for clinical application and could be implemented in future clinical trials to evaluate its relevance for predicting and monitoring response to ICI.
PD-1/PD-L1轴的免疫检查点抑制（ICI）在一部分转移性尿路上皮癌（UC）患者中显示出持久的反应。然而，肿瘤活检中的PD-L1表达不一定与对PD-1/PD-L1抑制剂的反应相关。因此，迫切需要一种可靠的预测生物标志物。在此，分析了晚期UC患者血液中循环肿瘤细胞（CTC）上PD-L1的表达。为此，使用掺入健康供体血样中的五种UC细胞系的细胞，建立了一种使用CellSearch®系统检测CTC上PD-L1表达的检测方法，并将其应用于UC患者的异质性队列。对49例晚期UC患者的血样进行了CTC计数。在16个CTC阳性样本中的10个（63%）中发现≥1个CTC中有PD-L1表达。观察到患者内和患者间关于CTC的PD-L1表达的异质性。此外，在15个CTC阳性样本中的4个（27%）中检测到波形蛋白表达的CTC，与PD-L1分析无关。CTC检测以及存在中度或强PD-L1表达的CTC均与较差的总生存期相关。对三名接受ICI的个体患者病程中的分析表明，除了CTC数量外，CTC上的PD-L1表达也可能潜在地表明疾病进展。这是第一项证明使用CellSearch®系统检测晚期UC患者中CTC-PD-L1表达的可行性的研究。该检测方法可随时用于临床应用，并可在未来的临床试验中实施，以评估其在预测和监测对ICI的反应方面的相关性。
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