背景：免疫检查点抑制剂（ICIs）可诱发免疫相关不良事件（irAE）。迫切需要预测 irAE 发生的液体生物标志物。我们之前开发了一种 ELISA 系统，用于特异性检测具有 PD-1 结合能力 (bsPD-L1) 的可溶性 PD-L1 (sPD-L1)。在这里，我们研究了接受 PD-1/PD-L1 阻断治疗的胃癌 (GC) 和非小细胞肺癌 (NSCLC) 中 sPD-L1 和 bsPD-L1 之间的关系及其与 irAE 的关联。方法：我们通过 ELISA 检测了 117 名 GC 患者术前和 72 名 NSCLC 患者 ICI 治疗前和治疗后 2 个月血浆样本中的 sPD-L1、bsPD-L1、基质金属蛋白酶 (MMP) 和促炎细胞因子水平。 PD-1，n = 48；抗 PD-L1，n = 24）。在用抗 PD-1/PD-L1 抗体 (Abs) 治疗的小鼠中，分别通过 ELISA 和免疫组织化学检查 sPD-L1 水平和 Abs 定位。结果：sPD-L1在GC患者中的检出频率高于NSCLC患者，而bsPD-L1在GC和NSCLC患者中的检出频率相似。 sPD-L1水平与IL-1α、IL-1β、TNF-α和IL-6水平相关，而bsPD-L1水平与MMP13、MMP3和IFN-γ水平相关。在 NSCLC 患者中，抗 PD-L1（而非抗 PD-1）治疗可增加 sPD-L1，这与 irAE 的发生相关，但与临床结果无关。在小鼠中，抗 PD-L1 Ab 转运至 F4/80 巨噬细胞中的溶酶体导致 sPD-L1 产生，而溶酶体降解抑制剂氯喹治疗和巨噬细胞耗竭可抑制 sPD-L1 产生。结论：抗 PD-L1 介导的溶酶体降解诱导 sPD-L1 产生，这可以作为预测抗 PD-L1 治疗期间 irAE 发展的指标。版权所有 © 2024 Kashiwada, Takano, Ando, Kuroda, Miyabe, Owada,宫永、浅间奥村、桥口、金泽、吉田、圣池、杰玛和岩井。

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs. Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively. Results:sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80+ macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion. Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment.Copyright © 2024 Kashiwada, Takano, Ando, Kuroda, Miyabe, Owada, Miyanaga, Asatsuma-Okumura, Hashiguchi, Kanazawa, Yoshida, Seike, Gemma and Iwai.