评估接受 PD-1/PD-L1 阻断治疗的癌症患者循环肿瘤细胞中 PD-L1 表达水平预测临床结局。
Assessment of PD-L1 Expression on Circulating Tumor Cells for Predicting Clinical Outcomes in Patients with Cancer Receiving PD-1/PD-L1 Blockade Therapies.
机构信息
Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, People's Republic of China.
CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterial and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, People's Republic of China.
出版信息
Oncologist. 2021 Dec;26(12):e2227-e2238. doi: 10.1002/onco.13981. Epub 2021 Sep 28.
BACKGROUND
Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade immunotherapies have changed the landscape of cancer therapy. However, the main limitation of these therapies is the lack of definitively predictive biomarkers to predict treatment response. Whether PD-L1 expression on circulating tumor cells (CTCs) is associated with the clinical outcomes of immunotherapy remains to be extensively investigated.
MATERIALS AND METHODS
One hundred fifty-five patients with different advanced cancers were enrolled in this study and treated with anti-PD-1/PD-L1 monoclonal antibodies. Using the Pep@MNPs method, CTCs were isolated and enumerated. The PD-L1 expression levels were analyzed by an immunofluorescence assay for semiquantitative assessment with four categories (negative, low, medium, and high).
RESULTS
Prior to immunotherapy, 81.93% (127/155) of patients had PD-L1-positive CTCs, and 71.61% (111/155) had at least one PD-L1-high CTC. The group with PD-L1-positive CTCs had a higher disease control rate (DCR) (71.56%, 91/127), with a DCR of only 39.29% (11/28) for the remaining individuals (p = .001). The objective response rate and DCR in PD-L1-high patients were higher than those in the other patients (32.44% vs. 13.64%, p = .018 and 75.68% vs. 40.91%, p < .0001, respectively). The reduction in the counts and ratios of PD-L1-positive CTCs and PD-L1-high CTCs reflected a beneficial response to PD-1/PD-L1 inhibitors. Furthermore, patients with PD-L1-high CTCs had significantly longer progression-free survival (4.9 vs. 2.2 months, p < .0001) and overall survival (16.1 vs. 9.0 months, p = .0235) than those without PD-L1-high CTCs.
CONCLUSION
The PD-L1 level on CTCs may serve as a clinically actionable biomarker for immunotherapy, and its dynamic changes could predict the therapeutic response.
IMPLICATIONS FOR PRACTICE
This study was designed to investigate the role of programmed death-ligand 1 (PD-L1) expression on circulating tumor cells in predicting and monitoring response to programmed death-1 (PD-1)/PD-L1 blockade immunotherapies in patients with advanced cancer. The results of the study showed that PD-L1-high-expression circulating tumor cells (CTCs) were both a predictive biomarker and a prognostic factor in patients with advanced cancer treated with anti-PD-1/PD-L1 monoclonal antibodies. These observations suggest that PD-L1 level on CTCs is a potential clinical biomarker for immunotherapy.
背景
程序性死亡-1（PD-1）和程序性死亡配体 1（PD-L1）阻断免疫疗法改变了癌症治疗的格局。然而，这些疗法的主要限制是缺乏明确的预测性生物标志物来预测治疗反应。PD-L1 在循环肿瘤细胞（CTC）上的表达是否与免疫治疗的临床结局相关，仍有待广泛研究。
材料和方法
本研究纳入了 155 名患有不同晚期癌症的患者，并接受了抗 PD-1/PD-L1 单克隆抗体治疗。使用 Pep@MNPs 方法分离和计数 CTCs。采用免疫荧光法分析 PD-L1 表达水平，分为四个类别（阴性、低、中、高）进行半定量评估。
结果
在免疫治疗前，81.93%（127/155）的患者有 PD-L1 阳性 CTCs，71.61%（111/155）的患者至少有一个 PD-L1 高 CTCs。PD-L1 阳性 CTCs 组的疾病控制率（DCR）更高（71.56%，91/127），而其余患者的 DCR 仅为 39.29%（11/28）（p=0.001）。PD-L1 高表达患者的客观缓解率和 DCR 均高于其他患者（32.44% vs. 13.64%，p=0.018 和 75.68% vs. 40.91%，p<0.0001，分别）。PD-L1 阳性 CTCs 和 PD-L1 高 CTCs 计数和比值的减少反映了对 PD-1/PD-L1 抑制剂的有益反应。此外，PD-L1 高 CTCs 患者的无进展生存期（4.9 个月 vs. 2.2 个月，p<0.0001）和总生存期（16.1 个月 vs. 9.0 个月，p=0.0235）明显长于无 PD-L1 高 CTCs 患者。
结论
CTC 上的 PD-L1 水平可能是免疫治疗的一种临床可操作的生物标志物，其动态变化可预测治疗反应。
临床意义
本研究旨在探讨程序性死亡配体 1（PD-L1）在循环肿瘤细胞上的表达在预测和监测接受抗 PD-1/PD-L1 单克隆抗体治疗的晚期癌症患者对程序性死亡-1（PD-1）/PD-L1 阻断免疫治疗反应中的作用。研究结果表明，PD-L1 高表达循环肿瘤细胞（CTC）是晚期癌症患者接受抗 PD-1/PD-L1 单克隆抗体治疗的预测性生物标志物和预后因素。这些观察结果表明，CTC 上的 PD-L1 水平是免疫治疗的一个潜在的临床生物标志物。
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