Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany.
Faculty of Biology, ALU, Freiburg, Germany.
JCI Insight. 2020 Mar 26;5(6):132334. doi: 10.1172/jci.insight.132334.
Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.
免疫检查点抑制剂（ICI）治疗在多种癌症实体的治疗中显示出显著的益处。然而，免疫相关的不良反应（irAEs）经常发生，并可能导致 ICI 治疗终止。微小 RNA-146a（miR-146a）在免疫细胞中具有调节功能。我们观察到，在两种不同的小鼠模型中，缺乏 miR-146a 的小鼠在几个 irAE 靶器官中比 WT 小鼠发展出更严重的 irAE。在接受 ICI 治疗后，miR-146a-/- 小鼠的 T 细胞激活和效应功能显著增加。此外，在接受 ICI 治疗的 miR-146a-/- 小鼠中，脾脏和发炎肠道中的中性粒细胞数量高度增加。miR-146a 模拟物的治疗给药可降低 irAE 的严重程度。为了验证我们在患者中的临床前发现，我们分析了 MIR146A 基因中的 SNP 对 167 名接受 ICI 治疗的患者 irAE 严重程度的影响。我们发现，导致 miR-146a 表达降低的 SNP rs2910164 与发生严重 irAE 的风险增加、无进展生存期缩短以及在基线和 ICI 治疗期间中性粒细胞计数增加相关。总之，我们将 miR-146a 确定为预防 ICI 介导的自身免疫失调的分子靶标。此外，我们确定了 MIR146A SNP rs2910164 作为预测接受 ICI 治疗的患者发生严重 irAE 发展的生物标志物。
