Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1⁺ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8⁺ T-cell responses. Our data identify a unique role for DCs in the PD-L1–PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1⁺ tumor cells.

抑制程序性死亡-1 (PD-1) 通路是癌症免疫治疗最有效的方法之一，但其机制基础仍不完全清楚。PD-1 与其配体 PD-L1 的结合部分通过抑制 CD28 信号传导来抑制 T 细胞功能。肿瘤细胞和浸润性骨髓细胞可以表达 PD-L1，其中骨髓细胞特别受关注，因为它们还表达 B7-1，一种 CD28 和 PD-L1 的配体。在这里，我们证明树突状细胞 (DC) 是 PD-L1 的关键来源，尽管 PD-L1 ⁺巨噬细胞的数量远远超过。DCs 中 PD-L1 的缺失，而不是巨噬细胞，极大地限制了肿瘤的生长并导致抗肿瘤 CD8 ^+增强T细胞反应。我们的数据确定了 DC 在 PD-L1-PD-1 调节轴中的独特作用，并有助于理解检查点阻断的治疗机制，长期以来一直认为这反映了 PD-L1 诱导的 T 细胞衰竭的逆转⁺肿瘤细胞。