Cancer Immunotherapy Discovery, Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Schlieren 8952, Switzerland.
Pharmaceutical Sciences, Biomarkers, Bioinformatics and Omics & Pathology, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel 4070, Switzerland.
Sci Transl Med. 2020 Mar 11;12(534). doi: 10.1126/scitranslmed.aav7431.
PD-L1/PD-1 blocking antibodies have demonstrated therapeutic efficacy across a range of human cancers. Extending this benefit to a greater number of patients, however, will require a better understanding of how these therapies instigate anticancer immunity. Although the PD-L1/PD-1 axis is typically associated with T cell function, we demonstrate here that dendritic cells (DCs) are an important target of PD-L1 blocking antibody. PD-L1 binds two receptors, PD-1 and B7.1 (CD80). PD-L1 is expressed much more abundantly than B7.1 on peripheral and tumor-associated DCs in patients with cancer. Blocking PD-L1 on DCs relieves B7.1 sequestration in cis by PD-L1, which allows the B7.1/CD28 interaction to enhance T cell priming. In line with this, in patients with renal cell carcinoma or non-small cell lung cancer treated with atezolizumab (PD-L1 blockade), a DC gene signature is strongly associated with improved overall survival. These data suggest that PD-L1 blockade reinvigorates DC function to generate potent anticancer T cell immunity.
PD-L1/PD-1 阻断抗体在多种人类癌症中显示出治疗效果。然而，要将这种益处扩展到更多的患者，就需要更好地了解这些疗法如何引发抗癌免疫。尽管 PD-L1/PD-1 轴通常与 T 细胞功能相关，但我们在这里证明树突状细胞 (DC) 是 PD-L1 阻断抗体的一个重要靶点。PD-L1 结合两个受体，PD-1 和 B7.1（CD80）。在癌症患者的外周和肿瘤相关 DC 中，PD-L1 的表达比 B7.1 丰富得多。阻断 DC 上的 PD-L1 可解除 PD-L1 在顺式中对 B7.1 的隔离，从而允许 B7.1/CD28 相互作用增强 T 细胞的启动。与此一致的是，在接受阿特珠单抗（PD-L1 阻断）治疗的肾细胞癌或非小细胞肺癌患者中，DC 基因特征与总生存期的改善强烈相关。这些数据表明，PD-L1 阻断可恢复 DC 功能，从而产生有效的抗癌 T 细胞免疫。
