NantHealth, Inc., 9920 Jefferson Blvd, Culver City, CA, United States; Department of Biochemistry and Molecular Medicine, Keck-USC School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA, United States; Department of Surgical Specialties, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, Japan.
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, Essen, Germany.
Biochem Biophys Res Commun. 2018 Jun 7;500(3):621-625. doi: 10.1016/j.bbrc.2018.04.120. Epub 2018 Apr 30.
Precision medicine and prediction of therapeutic response requires monitoring potential biomarkers before and after treatment. Liquid biopsies provide noninvasive prognostic markers such as circulating tumor DNA and RNA. Circulating tumor RNA (ctRNA) in blood is also used to identify mutations in genes of interest, but additionally, provides information about relative expression levels of important genes. In this study, we analyzed PD-L1 expression in ctRNA isolated from various cancer types. Tumors inhibit antitumor response by modulating the immune checkpoint proteins programmed death ligand 1 (PD-L1) and its cognate receptor PD1. The expression of these genes has been implicated in evasion of immune response and resistance to targeted therapies.
Blood samples were collected from gastric (GC), colorectal (CRC), lung (NSCLC), breast (BC), prostate cancer (PC) patients, and a healthy control group. ctRNA was purified from fractionated plasma, and following reverse transcription, levels of PD-L1 expression were analyzed using qPCR.
PD-L1 expression was detected in the plasma ctRNA of all cancer types at varying frequencies but no PD-L1 mRNA was detected in cancer-free individuals. The frequencies of PD-L1 expression were significantly different among the various cancer types but the median relative PD-L1 expression values were not significantly different. In 12 cases where plasma and tumor tissue were available from the same patients, there was a high degree of concordance between expression of PD-L1 protein in tumor tissues and PD-L1 gene expression in plasma, and both methods were equally predictive of response to nivolumab.
PD-L1 mRNA can be detected and quantitated in ctRNA of cancer patients. These results pave the way for further studies aimed at determining whether monitoring the levels of PD-L1 mRNA in blood can identify patients who are most likely to benefit from the conventional treatment.
精准医学和治疗反应预测需要在治疗前后监测潜在的生物标志物。液体活检提供了非侵入性的预后标志物，如循环肿瘤 DNA 和 RNA。血液中的循环肿瘤 RNA（ctRNA）也用于鉴定感兴趣基因的突变，但除此之外，还提供了有关重要基因相对表达水平的信息。在这项研究中，我们分析了从各种癌症类型中分离出的 ctRNA 中的 PD-L1 表达。肿瘤通过调节免疫检查点蛋白程序性死亡配体 1（PD-L1）及其同源受体 PD1 来抑制抗肿瘤反应。这些基因的表达与逃避免疫反应和对靶向治疗的耐药性有关。
从胃癌（GC）、结直肠癌（CRC）、肺癌（NSCLC）、乳腺癌（BC）、前列腺癌（PC）患者和健康对照组采集血液样本。从分馏的血浆中纯化 ctRNA，进行逆转录后，使用 qPCR 分析 PD-L1 表达水平。
在所有癌症类型的血浆 ctRNA 中均以不同的频率检测到 PD-L1 表达，但在无癌症个体中未检测到 PD-L1 mRNA。各种癌症类型之间 PD-L1 表达的频率存在显著差异，但中位数相对 PD-L1 表达值无显著差异。在 12 例来自同一患者的血浆和肿瘤组织可用的情况下，肿瘤组织中 PD-L1 蛋白的表达与血浆中 PD-L1 基因的表达之间具有高度一致性，并且两种方法均能同等预测对 nivolumab 的反应。
可以在癌症患者的 ctRNA 中检测到并定量 PD-L1 mRNA。这些结果为进一步研究奠定了基础，旨在确定监测血液中 PD-L1 mRNA 水平是否可以识别最有可能从常规治疗中受益的患者。
