State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, MOH Key Laboratory of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, China.
Front Immunol. 2018 Jul 30;9:1774. doi: 10.3389/fimmu.2018.01774. eCollection 2018.
Programmed death 1 (PD-1) and its two natural ligands PD-L1 and PD-L2 are responsible for delivering inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. In previous studies, PD-1 was found only expressed on the surface of immune cells, such as T cells and B cells while PD-1's ligands PD-L1 and PD-L2 were found expressed in some tumor cells. However, recent studies revealed intrinsic expression of PD-1 in melanoma and some other cancers. In melanoma cells, PD-1 can be activated by its ligand PD-L1 expressed by tumor cells, modulating downstream mammalian target of rapamycin signaling and promoting tumor growth independent of adaptive immunity. In addition to melanoma, PD-1 was also detected in liver cancer cells as well as in non-small lung cancer cells. Unlike its oncogenic functions in melanoma and hepatic carcinoma cells, PD-1 seemed to play a distinct role in lung cancer, as blockade of PD-1 instead promoted tumor cells proliferation. Tumor-intrinsic PD-1 expression seems to be widespread in many tumor types, according to our reanalysis on cancer transcriptomic and proteomic data. The multifaceted roles of PD-1 in tumor cells beyond immune checkpoint signaling may explain the differential therapeutic effects of anti-PD-1 and anti-PD-L1 drugs and provide crucial information when developing combinatorial approaches to enhance antitumor immunity.
程序性死亡受体 1（PD-1）及其两个天然配体 PD-L1 和 PD-L2 负责传递抑制信号，调节 T 细胞激活、耐受和免疫病理学之间的平衡。在之前的研究中，仅发现 PD-1 表达于免疫细胞表面，如 T 细胞和 B 细胞，而 PD-1 的配体 PD-L1 和 PD-L2 则表达于一些肿瘤细胞。然而，最近的研究揭示了 PD-1 在黑色素瘤和其他一些癌症中的内在表达。在黑色素瘤细胞中，PD-1 可以被肿瘤细胞表达的其配体 PD-L1 激活，调节下游哺乳动物雷帕霉素靶蛋白信号通路，并促进肿瘤生长，而不依赖于适应性免疫。除了黑色素瘤，PD-1 也在肝癌细胞和非小细胞肺癌细胞中被检测到。与 PD-1 在黑色素瘤和肝癌细胞中的致癌功能不同，PD-1 在肺癌中似乎发挥着独特的作用，因为阻断 PD-1 反而促进了肿瘤细胞的增殖。根据我们对癌症转录组和蛋白质组数据的重新分析，肿瘤内在的 PD-1 表达似乎在许多肿瘤类型中广泛存在。PD-1 在肿瘤细胞中的多方面作用超出了免疫检查点信号，这可能解释了抗 PD-1 和抗 PD-L1 药物的不同治疗效果，并在开发增强抗肿瘤免疫的联合治疗方法时提供了关键信息。
