Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Exp Mol Med. 2019 Aug 9;51(8):1-13. doi: 10.1038/s12276-019-0295-2.
Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8 T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.
程序性死亡蛋白-1/程序性死亡配体-1（PD-1/PD-L1）通路阻断是一种很有前途的癌症新疗法。尽管 PD-1/PD-L1 治疗在几种类型的癌症中已产生临床获益，但仍需要进一步研究来阐明药物疗效的预测生物标志物，并了解宿主和肿瘤细胞之间 PD-1/PD-L1 相互作用的基本机制。在这里，我们表明，肺癌细胞来源的外泌体表达 PD-L1，并通过降低 T 细胞活性和促进肿瘤生长来发挥免疫逃避作用。外泌体表面 PD-L1 的丰度代表了 PD-L1 在细胞表面的表达量。含有 PD-L1 的外泌体抑制 Jurkat T 细胞干扰素-γ（IFN-γ）的分泌。PD-L1 的敲除或在外泌体上的遮蔽可恢复 IFN-γ 的分泌。细胞表面无 PD-L1 的 PD-L1 过表达和含 PD-L1 的外泌体处理均增强了体内肿瘤的生长。从非小细胞肺癌患者血浆中分离的外泌体中存在 PD-L1，其在外泌体中的丰度与肿瘤组织中 PD-L1 阳性相关。外泌体可通过减少细胞因子的产生和诱导 CD8 T 细胞凋亡来损害免疫功能。我们的研究结果表明，表达 PD-L1 的肿瘤源性外泌体可能是肿瘤免疫逃逸的一个重要介质。
Zotero 插件
