Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Republic of Korea.
Medical Research Collaborating Center, Department of Biostatistics, Seoul National University Boramae Hospital, Seoul, Republic of Korea.
Diagn Pathol. 2020 Jun 4;15(1):69. doi: 10.1186/s13000-020-00979-z.
The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials.
We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines.
PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. "Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8 tumor-infiltrating lymphocytes (TILs)," and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3 TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3 TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(-) cell lines.
The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of "tumoral PD-L1/immune cell PD-L1/CD8 TILs" may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8 TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.
尽管免疫检查点 PD-1/PD-L1 抑制剂在临床试验中取得了令人鼓舞的结果，但 PD-L1 在胃癌中的预后潜力尚不清楚。
我们研究了 514 例连续接受手术切除的胃癌中程序性死亡配体 1（PD-L1）的预后意义。评估总生存率和无复发生存率。进行 PD-L1、CD8、FOXP3 和 PD-1 的免疫组织化学染色，以及通过原位杂交进行 EBV 编码的小 RNA 和多重 PCR 进行微卫星不稳定性（MSI）标记物的分子分组。此外，为了探索 PD-L1 固有的功能，我们在 5 种胃癌细胞系中进行了 PD-L1 特异性 siRNA 转染、细胞增殖、侵袭、迁移和凋亡检测。
101 例（20%）和 244 例（47%）患者肿瘤和免疫细胞呈 PD-L1（+）。多变量分析显示，“肿瘤 PD-L1（+）/免疫细胞 PD-L1（-）/CD8 肿瘤浸润淋巴细胞（TILs）”和更晚期肿瘤与整个队列的不良临床结局相关。此外，在 EBV 阳性和 MSI 高的肿瘤中，肿瘤 PD-L1（+）/FOXP3 TILs 与更差的临床结局相关。肿瘤 PD-L1（+）本身是 EBV 阳性肿瘤的不良预后因素，但在 MSI 高的肿瘤中并非如此，而 PD-L1（+）免疫细胞或 FOXP3 TILs 本身与预后良好相关。在两种 EBV（+）细胞系中，PD-L1 敲低抑制了胃癌细胞的增殖、侵袭和迁移，并增加了凋亡，这些在统计学上均具有显著性，但在三种 EBV（-）细胞系中并非如此。
尽管 PD-L1 在细胞基础检测中固有地促进癌细胞存活，但 PD-L1 的预后影响可能取决于肿瘤微环境以及 EBV 和 MSI 的状态。“肿瘤 PD-L1/免疫细胞 PD-L1/CD8 TILs”的联合可能是一个独立的预后因素。表现出更差预后的肿瘤 PD-L1（+）/免疫细胞 PD-L1（-）/CD8 TILs 可能有利于抗 PD-L1/PD-1 和抗细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）的联合治疗，从而促进效应 T 细胞攻击肿瘤。
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