Mann Steven A, Lopez-Beltran Antonio, Massari Francesco, Pili Roberto, Fiorentino Michelangelo, Koch Michael O, Kaimakliotis Hristos Z, Wang Lisha, Scarpelli Marina, Ciccarese Chiara, Moch Holger, Montironi Rodolfo, Cheng Liang
Departments of Pathology, Indiana University School of Medicine, Indianapolis. United States.
Unit of Anatomical Pathology, Faculty of Cordoba University, Cordoba, Spain and Champalimaud Clinical Center, Lisbon. Portugal.
Curr Drug Metab. 2017 Oct 16;18(8):700-711. doi: 10.2174/1389200218666170518162500.
Immune checkpoint inhibitors have revolutionized the treatment of many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent.
PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including Renal Cell Carcinoma (RCC) and urothelial carcinoma. Each FDAapproved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. The majority of PD-1/PDL1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers. There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles.
PD-1 is expressed on lymphocytes. PD-L1 is expressed on both tumor cells and immune cells. IHC staining appears in membranous fashion. A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies. Caution should be observed when employing tissue microarray techniques.
RCC has been the most studied of the genitourinary malignancies for PD-L1 expression. The atezolizumab- approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma. With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish.
免疫检查点抑制剂彻底改变了许多恶性肿瘤的治疗方式，在过去六年中，美国食品药品监督管理局（FDA）已批准了十多种新药。由于免疫检查点抑制剂治疗效果显著且可能产生致命的不良反应，因此收集有关FDA批准的肿瘤的预后和预测信息是谨慎之举。
PD-L1表达是一个不良预后因素，并且在包括肾细胞癌（RCC）和尿路上皮癌在内的多种肿瘤类型中，可预测PD-1和PD-L1抑制剂的更好反应。每种FDA批准的PD-1/PD-L1药物都与一种PD-L1免疫组织化学（IHC）检测方法配对。大多数PD-1/PD-L1抑制剂临床试验使用的是专有IHC抗体，其验证数据不明确。因此，需要更好地了解和应用PD-1/PD-L1 IHC生物标志物。最近有大量使用抗体克隆来表征肿瘤PD-1/PD-L1表达谱的出版物。
PD-1在淋巴细胞上表达。PD-L1在肿瘤细胞和免疫细胞上均有表达。IHC染色呈膜状。对于大多数研究而言，肿瘤细胞PD-L1染色阳性的临界值至少为5%。采用组织微阵列技术时应谨慎。
在泌尿生殖系统恶性肿瘤中，RCC是对PD-L1表达研究最多的肿瘤。阿特珠单抗批准的IHC检测方法独特之处在于，在尿路上皮癌中使用该检测方法时，仅对免疫细胞染色进行定量。熟悉当前的FDA指南、已发表的医学文献以及一般免疫组织化学注意事项后，免疫检查点生物标志物的应用将继续蓬勃发展。
