Koh Jiwon, Ock Chan-Young, Kim Jin Won, Nam Soo Kyung, Kwak Yoonjin, Yun Sumi, Ahn Sang-Hoon, Park Do Joong, Kim Hyung-Ho, Kim Woo Ho, Lee Hye Seung
Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 03080, Republic of Korea.
Department of Internal Medicine, Seoul National University Hospital, Jongno-gu, Seoul 03080, Republic of Korea.
Oncotarget. 2017 Apr 18;8(16):26356-26367. doi: 10.18632/oncotarget.15465.
We co-assessed PD-L1 expression and CD8+ tumor-infiltrating lymphocytes in gastric cancer (GC), and categorized into 4 microenvironment immune types. Immunohistochemistry (PD-L1, CD8, Foxp3, E-cadherin, and p53), PD-L1 mRNA in situ hybridization (ISH), microsatellite instability (MSI), and EBV ISH were performed in 392 stage II/III GCs treated with curative surgery and fluoropyrimidine-based adjuvant chemotherapy, and two public genome databases were analyzed for validation. PD-L1+ was found in 98/392 GCs (25.0%). The proportions of immune types are as follows: PD-L1+/CD8High, 22.7%; PD-L1-/CD8Low, 22.7%; PD-L1+/CD8Low, 2.3%; PD-L1-/CD8High, 52.3%. PD-L1+/CD8High type accounted for majority of EBV+ and MSI-high (MSI-H) GCs (92.0% and 66.7%, respectively), and genome analysis from public datasets demonstrated similar pattern. PD-L1-/CD8High showed the best overall survival (OS) and PD-L1-/CD8Low the worst (P < 0.001). PD-L1 expression alone was not associated with OS, however, PD-L1-/CD8High type compared to PD-L1+/CD8High was independent favorable prognostic factor of OS by multivariate analysis (P = 0.042). Adaptation of recent molecular classification based on EBV, MSI, E-cadherin, and p53 showed no significant survival differences. These findings support the close relationship between PD-L1/CD8 status based immune types and EBV+, MSI-H GCs, and their prognostic significance in stage II/III GCs.
我们共同评估了胃癌（GC）中PD-L1的表达和CD8 +肿瘤浸润淋巴细胞，并将其分为4种微环境免疫类型。对392例接受根治性手术和氟嘧啶类辅助化疗的II/III期GC患者进行了免疫组织化学（PD-L1、CD8、Foxp3、E-钙黏蛋白和p53）、PD-L1 mRNA原位杂交（ISH）、微卫星不稳定性（MSI）和EBV ISH检测，并分析了两个公共基因组数据库以进行验证。在392例GC患者中有98例（25.0%）检测到PD-L1+。免疫类型的比例如下：PD-L1 + /CD8高，22.7%；PD-L1 - /CD8低，22.7%；PD-L1 + /CD8低，2.3%；PD-L1 - /CD8高，52.3%。PD-L1 + /CD8高类型在EBV +和微卫星高度不稳定（MSI-H）的GC中占大多数（分别为92.0%和66.7%），公共数据集的基因组分析显示了类似的模式。PD-L1 - /CD8高类型的总生存期（OS）最佳，PD-L1 - /CD8低类型最差（P < 0.001）。单独的PD-L1表达与OS无关，然而，通过多变量分析，与PD-L1 + /CD8高类型相比，PD-L1 - /CD8高类型是OS的独立有利预后因素（P = 0.042）。基于EBV、MSI、E-钙黏蛋白和p53的最新分子分类调整显示生存差异无统计学意义。这些发现支持了基于PD-L1/CD8状态的免疫类型与EBV +、MSI-H GC之间的密切关系及其在II/III期GC中的预后意义。
