Garcia-Diaz Angel, Shin Daniel Sanghoon, Moreno Blanca Homet, Saco Justin, Escuin-Ordinas Helena, Rodriguez Gabriel Abril, Zaretsky Jesse M, Sun Lu, Hugo Willy, Wang Xiaoyan, Parisi Giulia, Saus Cristina Puig, Torrejon Davis Y, Graeber Thomas G, Comin-Anduix Begonya, Hu-Lieskovan Siwen, Damoiseaux Robert, Lo Roger S, Ribas Antoni
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Cell Rep. 2017 May 9;19(6):1189-1201. doi: 10.1016/j.celrep.2017.04.031.
PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter. PD-L2 responded equally to interferon beta and gamma and is regulated through both IRF1 and STAT3, which bind to the PD-L2 promoter. Analysis of biopsy specimens from patients with melanoma confirmed interferon signature enrichment and upregulation of gene targets for STAT1/STAT2/STAT3 and IRF1 in anti-PD-1-responding tumors. Therefore, these studies map the signaling pathway of interferon-gamma-inducible PD-1 ligand expression.
程序性死亡受体配体1（PD-L1）和程序性死亡受体配体2（PD-L2）是程序性死亡受体1（PD-1）免疫抑制检查点的配体，可通过干扰素暴露在肿瘤中诱导产生，从而导致免疫逃逸。这一过程对于基于PD-1阻断的免疫治疗很重要。我们研究了黑色素瘤细胞中参与干扰素诱导信号传导的特定分子，这些信号传导调节PD-L1和PD-L2的表达。这些研究表明，干扰素-γ-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1轴主要调节PD-L1的表达，其中IRF1与其启动子结合。PD-L2对干扰素β和γ的反应相同，并通过与PD-L2启动子结合的IRF1和STAT3进行调节。对黑色素瘤患者活检标本的分析证实，在抗PD-1反应性肿瘤中，干扰素特征富集以及STAT1/STAT2/STAT3和IRF1的基因靶点上调。因此，这些研究描绘了干扰素-γ诱导的PD-1配体表达的信号通路。
