Department of Pathology, Penn State College of Medicine, Hershey, PA, USA.
Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.
Sci Rep. 2020 Jan 29;10(1):1439. doi: 10.1038/s41598-020-58351-6.
Although advanced bladder cancer overall has a poor prognosis, a subset of patients demonstrate durable response to immune checkpoint inhibitors. Evidence shows that the response to checkpoint inhibitors may be associated with type and degree of immune infiltration in the tumor microenvironment. Here, we evaluated immune markers stratified by molecular subtypes and histologic variants. The study utilized a series of urothelial carcinomas (UCs) by tissue microarray, on which histologic variants and molecular subtypes had previously been established. PD1, CD3, CD8 and CD68 expression was evaluated by immunohistochemistry in tumor infiltrating immune cells, while PD-L1 expression in the tumor microenvironment was assessed. Each marker was scored semi-quantitatively (score 0-3). Tumors were clustered by marker scores using agglomerative methods, and associations among markers, histologies, and molecular subtypes were analyzed. PD-L1 expression in the tumor microenvironment significantly correlated with presence of CD3, CD8 and chronic inflammation. Urothelial carcinoma may be classified as either immune high or low based on marker expression. The immune high group is enriched in higher CD3, PD-L1, and genomically-unstable molecular subtype, suggesting it may respond to checkpoint inhibitors. We also identified a degree of intratumoral heterogeneity in immune markers in bladder cancer.
虽然晚期膀胱癌总体预后较差，但有一部分患者对免疫检查点抑制剂有持久的反应。有证据表明，检查点抑制剂的反应可能与肿瘤微环境中免疫浸润的类型和程度有关。在这里，我们根据分子亚型和组织学变异对免疫标志物进行了分层评估。该研究利用组织微阵列对一系列尿路上皮癌（UC）进行了评估，此前已经确定了这些 UC 的组织学变异和分子亚型。通过免疫组织化学评估肿瘤浸润免疫细胞中的 PD1、CD3、CD8 和 CD68 表达，同时评估肿瘤微环境中的 PD-L1 表达。每个标志物都进行了半定量评分（评分 0-3）。通过凝聚方法对标记物评分进行聚类，并分析标记物、组织学和分子亚型之间的关联。肿瘤微环境中 PD-L1 的表达与 CD3、CD8 和慢性炎症的存在显著相关。基于标志物表达，尿路上皮癌可分为免疫高或免疫低。免疫高组 CD3、PD-L1 和基因组不稳定的分子亚型较高，提示其可能对检查点抑制剂有反应。我们还在膀胱癌中发现了免疫标志物的一定程度的肿瘤内异质性。
