文章：

通过小RNA深度测序扩展多发性骨髓瘤中表达的miRNA和miRNA偏移RNA的种类

Reverse signaling via PD-L1 supports malignant cell growth and survival in classical Hodgkin lymphoma

原文发布日期：2019-02-19

DOI: 10.1038/s41408-019-0185-9

类型: Article

开放获取: 是

英文摘要：

Treatment with programmed death-1 (PD-1) blocking antibodies results in high overall response rates in refractory and relapsed classical Hodgkin lymphoma (cHL) patients, indicating that PD-1/PD-1 ligand interactions are integral to progression of this disease. Given the genetically driven increased PD-L1/2 expression in HL, we hypothesized that reverse signaling through PD-1 ligands may be a potential mechanism contributing to the growth and survival of Hodgkin Reed–Sternberg (HRS) cells in cHL. Our data show that engagement of PD-L1 using an agonistic monoclonal antibody increases cell survival and proliferation and reduces apoptosis in HL cell lines. We show that HL patients have significantly higher serum levels of soluble PD-1 than healthy controls, and find that both membrane-bound and soluble forms of PD-1 are able to induce PD-L1 reverse signaling in HL cell lines. PD-L1 signaling, which is associated with activation of the MAPK pathway and increased mitochondrial oxygen consumption, is reversed by PD-1 blockade. In summary, our data identify inhibition of reverse signaling through PD-L1 as an additional mechanism that accounts for clinical responses to PD-1 blockade in cHL.

摘要翻译： 

使用程序性死亡受体-1（PD-1）阻断抗体治疗难治性和复发性经典霍奇金淋巴瘤（cHL）患者可获得较高总体缓解率，这表明PD-1/PD-1配体相互作用是该疾病进展的关键环节。鉴于霍奇金淋巴瘤中遗传驱动导致的PD-L1/2表达增强，我们提出假说：通过PD-1配体的反向信号传导可能是促进cHL中霍奇金 Reed–Sternberg（HRS）细胞生长与存活的潜在机制。数据显示，使用激动性单克隆抗体结合PD-L1可增强HL细胞系的存活增殖并减少细胞凋亡。研究发现HL患者血清中可溶性PD-1水平显著高于健康对照组，且膜结合型与可溶性PD-1均能诱导HL细胞系中PD-L1反向信号传导。这种与MAPK通路激活及线粒体耗氧量增加相关的PD-L1信号传导，可被PD-1阻断剂逆转。总之，我们的研究揭示了通过抑制PD-L1反向信号传导是解释cHL中PD-1阻断剂临床疗效的又一新机制。

原文链接：

Reverse signaling via PD-L1 supports malignant cell growth and survival in classical Hodgkin lymphoma