PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways
PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways
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DOI：
10.1016/j.immuni.2019.11.003
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发表时间：
2019-12-17
期刊：
影响因子：
32.4
通讯作者：
Hui, Enfu
中科院分区：
文献类型：
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作者：
Zhao, Yunlong;Lee, Calvin K.;Hui, Enfu
与单药治疗相比，针对免疫检查点受体细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 和程序性细胞死亡 1 (PD-1) 或 CTLA-4 和 PD-1 配体 (PD-L1) 的联合免疫疗法表现出优异的抗肿瘤反应。在这里，我们研究了这种协同作用的分子基础。使用具有荧光读数的重构测定，我们发现 PD-L1 和 CTLA-4 配体 CD80 以顺式而非反式异二聚体。定量生物化学和细胞生物学检测表明，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) 上的 PD-L1 表达可阻止 CTLA-4 介导的 CD80 反式内吞作用。 Atezolizumab（抗 PD-L1）而非抗 PD-1 会降低 APC 上 CD80 的细胞表面表达，并且这种作用可通过联合阻断 CTLA-4 与 ipilimumab（抗 CTLA-4）而被抵消。因此，PD-L1通过抑制CTLA-4轴发挥免疫刺激作用；这对抗 PD-L1 和抗 CTLA-4 联合疗法的协同作用具有影响。
Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 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 assays with fluorescence readouts, we found that PD-L1 and the CTLA-4 ligand CD80 heterodimerize in 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 through distinct mechanisms but preserved the ability of CD80 to activate the T cell co-stimulatory receptor CD28. Furthermore, PD-L1 expression on antigen-presenting cells (APCs) prevented CTLA-4-mediated trans-endocytosis of CD80. Atezolizumab (anti-PD-L1), but not anti-PD-1, reduced cell surface expression of CD80 on APCs, and this effect was negated by co-blockade of CTLA-4 with ipilimumab (anti-CTLA-4). Thus, PD-L1 exerts an immunostimulatory effect by repressing the CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4 combination therapy.