Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
J Clin Pathol. 2021 Jan;74(1):53-57. doi: 10.1136/jclinpath-2020-206631. Epub 2020 May 29.
The advent of immune checkpoint inhibitor therapy has proven beneficial in a subset of high-grade urothelial carcinomas (HGUC) of the bladder. Although treatment selection is currently largely determined by programmed death-ligand 1 (PD-L1) status, multiple factors in the immune system may modulate the host immune response to HGUC and immunotherapy. In this pilot study, we used a transcriptomic approach to identify the immune milieu associated with PD-L1 expression to enhance our understanding of the HGUC immune evasion network.
The immune transcriptome of 40 HGUC cystectomy cases was profiled using the NanoString nCounter Human V.1.1 PanCancer Panel. All cases were assessed for associated PD-L1 status (SP263) using whole tissue sections. PD-L1 status was determined as high or low using 25% tumour and/or immune cell staining.
The most significantly differentially expressed gene was PD-L1 messenger RNA (), which strongly correlated with protein expression (r=0.720, p<0.001). The sensitivity, specificity, positive and negative predictive values of for PD-L1 expression were 85%, 96%, 92% and 93%, respectively. The PD-L1 associated gene signature also included complement components and and (innate immune system), proinflammatory cytokines and along with the immune response mediator among others. Pathway analysis determined enrichment of these genes in interleukin-10 production, lymphocyte chemotaxis and aberrant IFNγ, NF-κB and ERK signalling networks.
We report key genes and pathways in the immune transcriptome and their association with PD-L1 status, which may be involved in immune evasion of HGUC and warrants further investigation.
免疫检查点抑制剂治疗的出现已被证明对一部分高级别膀胱癌（HGUC）有益。尽管目前治疗选择主要取决于程序性死亡配体 1（PD-L1）状态，但免疫系统中的多个因素可能调节宿主对 HGUC 和免疫治疗的免疫反应。在这项初步研究中，我们使用转录组学方法来确定与 PD-L1 表达相关的免疫环境，以增强我们对 HGUC 免疫逃逸网络的理解。
使用 NanoString nCounter 人类 V.1.1 PanCancer 面板对 40 例 HGUC 膀胱切除术病例的免疫转录组进行了分析。所有病例均使用全组织切片评估相关 PD-L1 状态（SP263）。使用 25%的肿瘤和/或免疫细胞染色来确定 PD-L1 状态为高或低。
差异表达最显著的基因是 PD-L1 信使 RNA（mRNA）（），它与蛋白表达强烈相关（r=0.720，p<0.001）。用于 PD-L1 表达的敏感性、特异性、阳性预测值和阴性预测值分别为 85%、96%、92%和 93%。PD-L1 相关基因特征还包括补体成分和和（先天免疫系统）、促炎细胞因子和以及免疫反应调节剂等。通路分析确定了这些基因在白细胞介素 10 产生、淋巴细胞趋化性和异常 IFNγ、NF-κB 和 ERK 信号通路中的富集。
我们报告了免疫转录组中的关键基因和途径及其与 PD-L1 状态的关联，这些基因和途径可能参与了 HGUC 的免疫逃逸，值得进一步研究。
