Servei d'Oncologia Mèdica, Hospital del Mar, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
Servei de Patologia, Hospital del Mar, Barcelona, Spain; Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
Clin Lung Cancer. 2017 Nov;18(6):682-691.e5. doi: 10.1016/j.cllc.2017.04.014. Epub 2017 May 4.
Immune-checkpoint inhibitors against programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have shown remarkable therapeutic activity in non-small-cell lung cancer (NSCLC). However, biomarker-based patient selection remains a challenge. Our aim was to assess the heterogeneity of various immune markers between different tumor areas of surgically resected NSCLC specimens.
We included 94 adenocarcinoma (ADC) and 50 squamous cell carcinoma (SCC) specimens. Two distinct tumor areas of each tumor sample were selected and incorporated into tissue microarrays. PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was assessed using clone SP142 (Ventana). PDL1 gene amplification was assessed using fluorescence in situ hybridization. CD3 and CD8 densities were quantified using digital image-based analysis. Heterogeneity was assessed using kappa agreement index (KI) and intraclass correlation coefficient.
Prevalence of PD-L1 expression was 16.8% in TCs and 27.8% in ICs. Eleven tumors (7.6%) showed PDL1 amplification. In ADC, KI of PD-L1 TC and IC expression between cores was 0.465 and 0.260, compared with 0.274 and 0.124 in SCC, respectively. Higher concordance was observed for PDL1 amplification (KI, 0.647 in ADC and KI, 1 in SCC). Eleven (61.1%) of 18 amplified cores showed PD-L1 staining in < 5% of TCs. Intraclass correlation coefficients for CD3 and CD8 were 0.293 and 0.186 in ADC and 0.489 and 0.610 in SCC samples, respectively.
We found significant heterogeneity of PD-L1 expression in both ADC and SCC samples, especially in the IC compartment. Heterogeneous expression of PD-L1 could misclassify patients for PD-1/PD-L1-directed therapies.
针对程序性细胞死亡蛋白 1（PD-1）/程序性死亡配体 1（PD-L1）的免疫检查点抑制剂在非小细胞肺癌（NSCLC）中显示出显著的治疗活性。然而，基于生物标志物的患者选择仍然是一个挑战。我们的目的是评估手术切除的 NSCLC 标本不同肿瘤区域之间各种免疫标志物的异质性。
我们纳入了 94 例腺癌（ADC）和 50 例鳞状细胞癌（SCC）标本。每个肿瘤样本的两个不同肿瘤区域被选择并纳入组织微阵列。使用克隆 SP142（Ventana）评估肿瘤细胞（TCs）和免疫细胞（ICs）中的 PD-L1 表达。使用荧光原位杂交评估 PDL1 基因扩增。使用数字图像基于分析量化 CD3 和 CD8 密度。使用 Kappa 一致性指数（KI）和组内相关系数评估异质性。
TCs 中 PD-L1 表达的患病率为 16.8%，ICs 中为 27.8%。11 例肿瘤（7.6%）显示 PDL1 扩增。在 ADC 中，核心之间 PD-L1 TC 和 IC 表达的 KI 分别为 0.465 和 0.260，而 SCC 分别为 0.274 和 0.124。PDL1 扩增的一致性更高（KI，ADC 为 0.647，SCC 为 1）。18 个扩增核心中有 11 个（61.1%）在<5%的 TCs 中显示 PD-L1 染色。ADC 和 SCC 样本中 CD3 和 CD8 的组内相关系数分别为 0.293 和 0.186，以及 0.489 和 0.610。
我们发现 ADC 和 SCC 样本中 PD-L1 表达存在显著异质性，特别是在 IC 区。PD-L1 的异质表达可能会错误分类接受 PD-1/PD-L1 导向治疗的患者。
