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程序性细胞死亡蛋白PD-1与程序性细胞死亡配体PD-L1对于肿瘤免疫逃逸发挥至关重要的作用。三阴性乳腺癌与其他乳腺癌相比，已被证实PD-L1表达水平显著较高。 2020年4月3日，英国《自然》旗下《自然通讯》在线发表中山大学附属肿瘤医院、中山大学附属第六医院、中山大学孙逸仙纪念医院、中山大学附属第一医院的研究报告，发现核仁磷酸蛋白NPM1可以提高三阴性乳腺癌的PD-L1转录水平，并且抑制T淋巴细胞活性，从而促进三阴性乳腺癌的免疫逃避。 该研究发现NPM1可以结合至三阴性乳腺癌细胞的PD-L1转录起始位点DNA序列，并且激活PD-L1转录，从而抑制T淋巴细胞离体和在体活性。 此外，该研究还证实，多腺苷二磷酸核糖聚合酶PARP1通过与NPM1的PD-L1转录起始位点DNA序列核酸结合区发生相互作用，可以抑制PD-L1转录。PARP1抑制剂奥拉帕利可以提高三阴性乳腺癌的PD-L1表达水平，从而充分PD-L1抑制剂的疗效。 因此，该研究结果表明，NPM1作为三阴性乳腺癌的PD-L1转录调节因子，有望成为新的治疗靶点，有助于提高三阴性乳腺癌的免疫治疗效果。 相关阅读 Nat Commun. 2020 Apr 3. [Epub ahead of print] NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer. Ge Qin, Xin Wang, Shubiao Ye, Yizhuo Li, Miao Chen, Shusen Wang, Tao Qin, Changlin Zhang, Yixin Li, Qian Long, Huabin Hu, Dingbo Shi, Jiaping Li, Kai Zhang, Qinglian Zhai, Yanlai Tang, Tiebang Kang, Ping Lan, Fangyun Xie, Jianjun Lu, Wuguo Deng. Sun Yat-sen University Cancer Center, Guangzhou, China; The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 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. DOI: 10.1038/s41467-020-15364-z
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