Angell H K, Lee J, Kim K-M, Kim K, Kim S-T, Park S H, Kang W K, Sharpe A, Ogden J, Davenport A, Hodgson D R, Barrett J C, Kilgour E
Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Oncoimmunology. 2018 Dec 10;8(2):e1544442. doi: 10.1080/2162402X.2018.1544442. eCollection 2019.
This study investigates the association of PD-L1 expression and immune cell infiltrates and their impact on clinical outcome, in addition to their overlap with microsatellite instability (MSI), HER2 and ATM molecular subgroups of gastric cancer (GC). PD-L1 membrane expression on tumour cells (TC) and infiltrating immune cells (IC), CD3 + T-lymphocytes, CD8+ cytotoxic T-cells, ATM and HER2 were assessed by immunohistochemistry (IHC) in the ACRG (Asian Cancer Research Group) GC cohort (N = 380). EBV status was determined using hybridization and MSI status was performed using PCR and MLH1 IHC. The PD-L1 segment was associated with increased T-cell infiltrates, while the MSI-high segment was enriched for PD-L1, CD3, and CD8. Multivariate analysis confirmed PD-L1 positivity, high CD3 and high CD8 as independent prognostic factors for both disease-free survival and overall survival (all p < 0.05). Patients with MSI-high tumours had better overall survival by both univariate and multivariate analysis. The ATM-low and HER2-high subgroups differed markedly in their immune profile; the ATM-low subgroups enriched for MSI, PD-L1 positivity and CD8 + T-cells, while the HER2 segment was enriched for MSS, with no enrichment for immune markers. Hence, we demonstrate a molecular profiling approach that can divide GC into four molecular subgroups, namely ATM-low, HER2-high, PD-L1 positive and MSI-high with differing levels of immune infiltrates and prognostic significance which may help to stratify patients for response to targeted therapies.
本研究调查了程序性死亡配体1（PD-L1）表达与免疫细胞浸润之间的关联及其对临床结局的影响，此外还研究了它们与胃癌（GC）的微卫星不稳定性（MSI）、人表皮生长因子受体2（HER2）和共济失调毛细血管扩张症突变基因（ATM）分子亚组的重叠情况。通过免疫组织化学（IHC）对亚洲癌症研究小组（ACRG）GC队列（N = 380）中的肿瘤细胞（TC）和浸润免疫细胞（IC）上的PD-L1膜表达、CD3 + T淋巴细胞、CD8 + 细胞毒性T细胞、ATM和HER2进行评估。使用杂交法确定EBV状态，使用聚合酶链反应（PCR）和错配修复蛋白MLH1免疫组化检测MSI状态。PD-L1片段与T细胞浸润增加相关，而MSI高片段富含PD-L1、CD3和CD8。多变量分析证实，PD-L1阳性、高CD3和高CD8是无病生存期和总生存期的独立预后因素（所有p < 0.05）。单变量和多变量分析均显示，MSI高肿瘤患者的总生存期更好。ATM低和HER2高亚组的免疫特征存在显著差异；ATM低亚组富含MSI、PD-L1阳性和CD8 + T细胞，而HER2片段富含微卫星稳定（MSS），免疫标志物无富集。因此，我们展示了一种分子分析方法，可以将GC分为四个分子亚组，即ATM低、HER2高、PD-L1阳性和MSI高，它们具有不同程度的免疫浸润和预后意义，这可能有助于对患者进行分层，以指导靶向治疗反应。
