Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Dev Cell. 2022 Feb 7;57(3):329-343.e7. doi: 10.1016/j.devcel.2022.01.002. Epub 2022 Jan 31.
Tumor-derived extracellular vesicles (TEVs) suppress the proliferation and cytotoxicity of CD8 T cells, thereby contributing to tumor immune evasion. Here, we report that the adhesion molecule intercellular adhesion molecule 1 (ICAM-1) co-localizes with programmed death ligand 1 (PD-L1) on the exosomes; both ICAM-1 and PD-L1 are upregulated by interferon-γ. Exosomal ICAM-1 interacts with LFA-1, which is upregulated in activated T cells. Blocking ICAM-1 on TEVs reduces the interaction of TEVs with CD8 T cells and attenuates PD-L1-mediated suppressive effects of TEVs. During this study, we have established an extracellular vesicle-target cell interaction detection through SorTagging (ETIDS) system to assess the interaction between a TEV ligand and its target cell receptor. Using this system, we demonstrate that the interaction of TEV PD-L1 with programmed cell death 1 (PD-1) on T cells is significantly reduced in the absence of ICAM-1. Our study demonstrates that ICAM-1-LFA-1-mediated adhesion between TEVs and T cells is a prerequisite for exosomal PD-L1-mediated immune suppression.
肿瘤来源的细胞外囊泡 (TEV) 抑制 CD8 T 细胞的增殖和细胞毒性，从而促进肿瘤免疫逃逸。在这里，我们报告黏附分子细胞间黏附分子 1 (ICAM-1) 与程序性死亡配体 1 (PD-L1) 在细胞外囊泡上共定位；干扰素-γ可上调 ICAM-1 和 PD-L1。细胞外囊泡上的 ICAM-1 与在活化 T 细胞中上调的 LFA-1 相互作用。阻断 TEV 上的 ICAM-1 可减少 TEV 与 CD8 T 细胞的相互作用，并减弱 TEV 介导的 PD-L1 抑制作用。在这项研究中，我们建立了一种通过 SorTagging（ETIDS）系统检测细胞外囊泡-靶细胞相互作用的方法，以评估 TEV 配体与其靶细胞受体之间的相互作用。使用该系统，我们证明在没有 ICAM-1 的情况下，TEV PD-L1 与 T 细胞上的程序性细胞死亡 1 (PD-1) 的相互作用显著减少。我们的研究表明，TEV 和 T 细胞之间的 ICAM-1-LFA-1 介导的黏附是细胞外 PD-L1 介导的免疫抑制的先决条件。
