ERK Inhibition Improves Anti-PD-L1 Immune Checkpoint Blockade in Preclinical Pancreatic Ductal Adenocarcinoma.
ERK Inhibition Improves Anti-PD-L1 Immune Checkpoint Blockade in Preclinical Pancreatic Ductal Adenocarcinoma.
复制标题
ERK抑制改善临床前胰腺导管腺癌抗PD-L1免疫检查点阻断。
DOI：
10.1158/1535-7163.mct-20-1112
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发表时间：
2021-10
影响因子：
5.7
通讯作者：
Lewis JS
中科院分区：
文献类型：
--
作者：
Henry KE;Mack KN;Nagle VL;Cornejo M;Michel AO;Fox IL;Davydova M;Dilling TR;Pillarsetty N;Lewis JS
胰腺导管腺癌（PDAC）患者不能从沿着PD-1/PD-L1轴的免疫检查点阻断（ICB）中获益。PDAC中PD-L1表达的变化表明PD-L1靶向治疗的潜在进入问题。为了监测PD-L1靶向治疗的靶向结合，我们生成了用锆-89（89 Zr）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[89 Zr]Zr-DFO-抗PD-L1作为工具，以非侵入性方式评估是否可利用MAPK信号级联的操纵来调节PD-L1表达，从而调节PDAC中的免疫结局。在这项研究中，我们观察到MEK或ERK的抑制足以增加PD-L1表达，我们假设这可以用于抗PD-L1免疫检查点治疗。我们发现，ERK抑制和抗PD-L1治疗的组合确实对应于PDAC的同基因小鼠模型中总存活率的显著改善。此外，免疫组织化学分析表明，生存的好处可能是CD 8 + 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，并解决具有挑战性的恶性肿瘤（如PDAC）的治疗差距。
Pancreatic ductal adenocarcinoma (PDAC) patients 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. In order 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 non-invasively 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 indeed corresponded with a significant improvement of overall survival in a syngeneic mouse model of PDAC. Furthermore, immunohistochemical 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.