PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression
PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression
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DOI：
10.1172/jci96061
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发表时间：
2018-02-01
影响因子：
15.9
通讯作者：
Fu, Yang-Xin
中科院分区：
文献类型：
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作者：
Tang, Haidong;Liang, Yong;Fu, Yang-Xin
肿瘤细胞上的程序性死亡配体1（PD-L1）表达对于T细胞损伤至关重要，PD-L1阻断疗法在几项临床研究中显示出前所未有的持久反应。尽管肿瘤细胞上PD-L1的高表达与Ab阻断后更好的免疫应答相关，但一些PD-L1阴性患者也对这种治疗有反应。在本研究中，我们探讨了肿瘤或宿主细胞上的PD-L1是否是2种不同小鼠肿瘤模型中抗PD-L1介导治疗所必需的。在整个肿瘤组织中使用实时成像，我们发现抗PD-L1 Ab在肿瘤组织中积累，而不管肿瘤细胞上PD-L1表达的状态如何。我们进一步观察到，虽然肿瘤细胞上的PD-L1在很大程度上与对检查点阻断的反应无关，但宿主骨髓细胞中的PD-L1对这种反应至关重要。此外，PD-L1信号在特定的抗原呈递细胞（APC）中负调节和抑制T细胞活化。肿瘤内的PD-L1阻断不足以介导消退，因为限制T细胞运输降低了阻断的功效。总之，这些发现表明，在APC中而不是在肿瘤细胞上表达的PD-L1在检查点阻断治疗中起着至关重要的作用，为这种治疗的机制提供了深入了解。
Programmed death-ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1-negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti-PD-L1-mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti-PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.