Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.
Gastric Cancer. 2021 May;24(3):611-623. doi: 10.1007/s10120-020-01151-8. Epub 2021 Feb 20.
Immunotherapy targeting PD-1 provides a limited survival benefit in patients with unresectable advanced or recurrent gastric cancer (GC). Beside PD-L1, the expression of inhibitory ligands such as CEACAM-1 and LSECtin on GC cells account for this limitation. Here we assessed their expression and immune suppressive effect in GC patients.
Using multiplexed immunohistochemistry staining, we evaluated the distribution of different inhibitory ligands, including PD-L1, CEACAM-1, LSECtin, and MHC class II, in 365 GC patients. We analyzed their correlations and overall survival (OS) based on the expression of each inhibitory ligand and the independent prognostic factors that affect OS. Subsequently, we evaluated the additive effect of anti-PD-1 mAb or anti-PD-L1 mAb with/without anti-Lag-3 mAb with/without anti-Tim-3 mAb in cytotoxic assay using tumor-antigen specific CTL clones against GC cell lines.
Co-expression of the inhibitory ligands for PD-1, Tim-3, and Lag-3 was observed in the largest proportion (34.7%). CEACAM-1, LSECtin, and MHC class II expression showed significant correlation with PD-L1 expression and OS. Multivariable analysis demonstrated that CEACAM-1 low is an independent prognostic factor. Furthermore, combining dual and triple ICIs yielded additive effect on cytotoxicity of CTL clones against each immune inhibitory ligand positive GC cell lines.
Our findings suggested that the expression of inhibitory ligands for Tim-3 and Lag-3 on GC cells serve as potential biomarkers to predict the response to anti-PD-1 therapy and the combinatorial immunotherapy with ICIs targeting for PD-1, Tim-3, and Lag-3 has a therapeutic potential for GC patients.
针对 PD-1 的免疫疗法为不可切除的晚期或复发性胃癌（GC）患者提供了有限的生存获益。除了 PD-L1 之外，GC 细胞上抑制性配体如 CEACAM-1 和 LSECtin 的表达也是导致这种限制的原因。在这里，我们评估了它们在 GC 患者中的表达和免疫抑制作用。
我们使用多重免疫组化染色评估了 365 名 GC 患者中不同抑制性配体（包括 PD-L1、CEACAM-1、LSECtin 和 MHC Ⅱ类）的分布。我们根据每种抑制性配体的表达以及影响 OS 的独立预后因素分析了它们的相关性和总生存期（OS）。随后，我们使用针对 GC 细胞系的肿瘤抗原特异性 CTL 克隆，在细胞毒性测定中评估了抗 PD-1 mAb 或抗 PD-L1 mAb 与/或抗 Lag-3 mAb 与/或抗 Tim-3 mAb 的联合应用的附加效果。
观察到 PD-1、Tim-3 和 Lag-3 的抑制性配体的共表达比例最大（34.7%）。CEACAM-1、LSECtin 和 MHC Ⅱ类表达与 PD-L1 表达和 OS 呈显著相关。多变量分析表明 CEACAM-1 低是独立的预后因素。此外，双重和三重 ICI 的联合应用对 CTL 克隆对每种免疫抑制性配体阳性 GC 细胞系的细胞毒性具有相加作用。
我们的研究结果表明，GC 细胞上 Tim-3 和 Lag-3 的抑制性配体的表达可作为预测抗 PD-1 治疗反应的潜在生物标志物，并且针对 PD-1、Tim-3 和 Lag-3 的 ICI 联合免疫治疗对 GC 患者具有治疗潜力。
