美国加利福尼亚大学圣地亚哥分校Enfu Hui研究组发现，PD-L1:CD80顺式异源二聚体在抑制程序性细胞死亡1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）通路的同时，触发共刺激受体CD28。相关论文11月19日在线发表在《免疫学》上。

研究人员检测了联合免疫疗法协同作用的分子基础。使用带有荧光读数的重组实验，他们发现PD-1配体（PD-L1）和CTLA-4配体CD80异二聚体形成顺式而不是反式构象。定量生物化学和细胞生物学分析表明PD-L1：CD80顺式异二聚化通过不同的机制抑制PD-L1：PD-1和CD80：CTLA-4相互作用，但保留了CD80激活T细胞共刺激受体CD28的能力。此外，抗原呈递细胞（APC）上PD-L1的表达阻止了CTLA-4介导的CD80的反向胞吞作用。Atezolizumab（抗PD-L1）而非抗PD-1降低了APC上CD80在细胞表面的表达，这种作用被CTLA-4与ipilimumab（抗CTLA-4）的共阻断作用所抵消。因此，PD-L1通过抑制CTLA-4轴发挥免疫刺激作用。这暗示了抗PD-L1和抗CTLA-4联合治疗的协同作用。

此外，针对免疫检查点受体的CTLA-4和PD-1或CTLA-4和PD-L1的联合免疫疗法与单药治疗相比表现出优异的抗肿瘤反应。

附：英文原文

Title: PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways

Author: Yunlong Zhao, Calvin K. Lee, Chia-Hao Lin, Rodrigo B. Gassen, Xiaozheng Xu, Zhe Huang, Changchun Xiao, Cristina Bonorino, Li-Fan Lu, Jack D. Bui, Enfu Hui

Issue&Volume: November 19, 2019

Abstract: Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associatedprotein 4 (CTLA-4) and programmed cell death 1 (PD-1), or CTLA-4 and the PD-1 ligand(PD-L1) exhibits superior anti-tumor responses compared with single-agent therapy.Here, we examined the molecular basis for this synergy. Using reconstitution assayswith fluorescence readouts, we found that PD-L1 and the CTLA-4 ligand CD80 heterodimerizein cis but not trans. Quantitative biochemistry and cell biology assays revealed that PD-L1:CD80 cis-heterodimerization inhibited both PD-L1:PD-1 and CD80:CTLA-4 interactions throughdistinct mechanisms but preserved the ability of CD80 to activate the T cell co-stimulatoryreceptor CD28. Furthermore, PD-L1 expression on antigen-presenting cells (APCs) preventedCTLA-4-mediated trans-endocytosis of CD80. Atezolizumab (anti-PD-L1), but not anti-PD-1, reduced cell surfaceexpression of CD80 on APCs, and this effect was negated by co-blockade of CTLA-4 withipilimumab (anti-CTLA-4). Thus, PD-L1 exerts an immunostimulatory effect by repressingthe CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4combination therapy.

DOI: 10.1016/j.immuni.2019.11.003

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30461-3