Patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint blockade (ICB) along the PD-1/PD-L1 axis. Variable PD-L1 expression in PDAC indicates a potential access issue of PD-L1–targeted therapy. To monitor target engagement of PD-L1–targeted therapy, we generated a PD-L1–targeted PET tracer labeled with zirconium-89 (89Zr). As the MAPK signaling pathway (MEK and ERK) is known to modulate PD-L1 expression in other tumor types, we used [89Zr]Zr-DFO-anti–PD-L1 as a tool to noninvasively assess whether manipulation of the MAPK signaling cascade could be leveraged to modulate PD-L1 expression and thereby immunotherapeutic outcomes in PDAC. In this study, we observed that the inhibition of MEK or ERK is sufficient to increase PD-L1 expression, which we hypothesized could be leveraged for anti–PD-L1 immune checkpoint therapy. We found that the combination of ERK inhibition and anti–PD-L1 therapy corresponded with a significant improvement of overall survival in a syngeneic mouse model of PDAC. Furthermore, IHC analysis indicates that the survival benefit may be CD8+ T-cell mediated. The therapeutic and molecular imaging tool kit developed could be exploited to better structure clinical trials and address the therapeutic gaps in challenging malignancies such as PDAC.

中文翻译：

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ERK 抑制可改善临床前胰管腺癌中的抗 PD-L1 免疫检查点阻断


胰腺导管腺癌 (PDAC) 患者不会从 PD-1/PD-L1 轴上的免疫检查点阻断 (ICB) 中获益。 PDAC 中 PD-L1 表达的变化表明 PD-L1 靶向治疗存在潜在的准入问题。为了监测 PD-L1 靶向治疗的靶点参与情况，我们生成了一种用锆 89 (89Zr) 标记的 PD-L1 靶向 PET 示踪剂。由于已知 MAPK 信号通路（MEK 和 ERK）可调节其他肿瘤类型中的 PD-L1 表达，因此我们使用 [89Zr]Zr-DFO-anti-PD-L1 作为工具来无创评估 MAPK 信号级联的操纵是否有效可用于调节 PD-L1 表达，从而调节 PDAC 的免疫治疗结果。在这项研究中，我们观察到 MEK 或 ERK 的抑制足以增加 PD-L1 的表达，我们假设可以将其用于抗 PD-L1 免疫检查点治疗。我们发现，ERK 抑制和抗 PD-L1 疗法的结合可显着改善 PDAC 同基因小鼠模型的总生存期。此外，IHC 分析表明生存获益可能是 CD8+ T 细胞介导的。开发的治疗和分子成像工具包可用于更好地构建临床试验并解决 PDAC 等具有挑战性的恶性肿瘤的治疗差距。