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.

中文翻译：

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宿主细胞上的 PD-L1 对于 PD-L1 阻断介导的肿瘤消退至关重要


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 阻断疗法在多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 的较高表达与 Ab 阻断后更好的免疫反应相关，但一些 PD-L1 阴性患者也对这种治疗有反应。在当前的研究中，我们在两种不同的小鼠肿瘤模型中探讨了肿瘤或宿主细胞上的 PD-L1 是否对于抗 PD-L1 介导的治疗至关重要。通过对整个肿瘤组织进行实时成像，我们发现无论肿瘤细胞上 PD-L1 的表达状态如何，抗 PD-L1 Ab 都会在肿瘤组织中积聚。我们进一步观察到，虽然肿瘤细胞上的 PD-L1 对于检查点阻断的反应在很大程度上是可有可无的，但宿主骨髓细胞中的 PD-L1 对于这种反应至关重要。此外，特定抗原呈递细胞 (APC) 中的 PD-L1 信号传导负向调节并抑制 T 细胞激活。肿瘤内的 PD-L1 阻断不足以介导消退，因为限制 T 细胞运输会降低阻断的功效。总之，这些研究结果表明，PD-L1 在 APC 中表达，而不是在肿瘤细胞上表达，在检查点阻断疗法中发挥着重要作用，从而提供了对该疗法机制的深入了解。