Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Nat Commun. 2020 Apr 3;11(1):1669. doi: 10.1038/s41467-020-15364-z.
Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.
程序性死亡蛋白-1（PD-1）/程序性死亡配体-1（PD-L1）相互作用在肿瘤相关免疫逃逸中起着至关重要的作用。在这里，我们验证了三阴性乳腺癌（TNBC）比其他亚型具有更高的 PD-L1 表达。然后我们发现核磷蛋白（NPM1）在 TNBC 细胞中特异性结合 PD-L1 启动子，并激活 PD-L1 转录，从而抑制体外和体内 T 细胞的活性。此外，我们证明 PARP1 通过与 NPM1 的核酸结合域相互作用来抑制 PD-L1 转录，这对于 NPM1 在 PD-L1 启动子上的结合是必需的。一致地，PARP1 抑制剂奥拉帕利提高了 TNBC 中的 PD-L1 表达，并与抗 PD-L1 治疗产生更好的效果。总之，我们的研究揭示了 NPM1 是 TNBC 中 PD-L1 的转录调节剂，这可能为增强癌症免疫治疗的疗效提供潜在的治疗策略。
