Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1– and PD-1–deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti–PD-1 alone or in combination with anti–CTLA-4. Thus, PD-L1–expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.

中文翻译：

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PD-L1 的宿主表达决定 PD-L1 通路阻断介导的肿瘤消退的功效


程序性死亡 1 受体（PD-L1、B7-H1）和程序性细胞死亡蛋白 1 (PD-1) 通路阻断是一种有前景的癌症治疗方法。然而，宿主和肿瘤 PD-L1 和 PD-1 信号传导对 PD-L1 和 PD-1 阻断的治疗效果的机制贡献仍然难以捉摸。在这里，我们评估了 3 种对 PD-L1 阻断敏感性不同的荷瘤小鼠模型，并证明 PD-L1 阻断对免疫缺陷小鼠以及 PD-L1 和 PD-1 缺陷小鼠的治疗效果丧失。相比之下，肿瘤细胞中 PD-L1 的敲除和过表达都不会对 PD-L1 阻断功效产生影响。人类和小鼠研究表明，肿瘤微环境和引流淋巴结中的树突状细胞和巨噬细胞具有高水平的功能性 PD-L1 表达。此外，卵巢癌和黑色素瘤患者的树突状细胞和巨噬细胞上的 PD-L1 表达与单独使用抗 PD-1 或​​与抗 CTLA-4 联合治疗的疗效相关。因此，表达 PD-L1 的树突状细胞和巨噬细胞可能从机制上塑造并预测 PD-L1/PD-1 阻断的临床疗效。