Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression.
Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression.
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干扰素受体信号通路调节PD-L1和PD-L2表达。
DOI：
10.1016/j.celrep.2017.04.031
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发表时间：
2017-05-09
期刊：
影响因子：
8.8
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Garcia-Diaz A;Shin DS;Moreno BH;Saco J;Escuin-Ordinas H;Rodriguez GA;Zaretsky JM;Sun L;Hugo W;Wang X;Parisi G;Saus CP;Torrejon DY;Graeber TG;Comin-Anduix B;Hu-Lieskovan S;Damoiseaux R;Lo RS;Ribas A
PD-L1和PD-L2是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，导致免疫逃避。这一过程对于基于PD-1阻断的免疫治疗非常重要。我们检测了参与干扰素诱导的信号传导的特异性分子，该信号传导调节黑色素瘤细胞中PD-L1和PD-L2的表达。这些研究表明，干扰素-γ-JAK 1/JAK 2-STAT 1/STAT 2/STAT 3-IRF 1轴主要调节PD-L1表达，IRF 1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IRF 1和STAT 3进行调节。对来自黑色素瘤患者的活检标本的分析证实了干扰素特征富集和抗PD-1应答肿瘤中STAT 1/STAT 2/STAT 3和IRF 1的基因靶点上调。因此，这些研究绘制了干扰素-γ诱导的PD-1配体表达的信号传导途径。Garcia-Diaz等人进行了一项小发夹RNA筛选以及遗传和功能研究，以绘制干扰素γ暴露后导致黑色素瘤细胞上反应性PD-L1和PD-L2的信号传导途径。作者强调了JAK 1/JAK 2-STAT 1/STAT 2/STAT 3-IRF 1轴对PD-1阻断治疗临床反应的重要性。
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. Garcia-Diaz et al. performed a small hairpin RNA screen and genetic and functional studies to map the signaling pathways that result in reactive PD-L1 and PD-L2 on melanoma cells upon interferon gamma exposure. The authors highlight the importance of the JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis for clinical responses to PD-1 blockade therapy.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
4.3
作者：
Kutmon M;van Iersel MP;Bohler A;Kelder T;Nunes N;Pico AR;Evelo CT
通讯作者：
Evelo CT
影响因子：
11.2
作者：
Dunn, GP;Sheehan, KCF;Schreiber, RD
通讯作者：
Schreiber, RD
影响因子：
3.5
作者：
Lee, SJ;Jang, BC;Choi, IH
通讯作者：
Choi, IH
影响因子：
6.6
作者：
Escuin-Ordinas, Helena;Atefi, Mohammad;Ribas, Antoni
通讯作者：
Ribas, Antoni