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　　程序性細(xì)胞死亡蛋白PD-1與程序性細(xì)胞死亡配體PD-L1對于腫瘤免疫逃逸發(fā)揮至關(guān)重要的作用。三陰性乳腺癌與其他乳腺癌相比，已被證實(shí)PD-L1表達(dá)水平顯著較高。

　　2020年4月3日，英國《自然》旗下《自然通訊》在線發(fā)表中山大學(xué)附屬腫瘤醫(yī)院、中山大學(xué)附屬第六醫(yī)院、中山大學(xué)孫逸仙紀(jì)念醫(yī)院、中山大學(xué)附屬第一醫(yī)院的研究報(bào)告，發(fā)現(xiàn)核仁磷酸蛋白NPM1可以提高三陰性乳腺癌的PD-L1轉(zhuǎn)錄水平，并且抑制T淋巴細(xì)胞活性，從而促進(jìn)三陰性乳腺癌的免疫逃避。

　　該研究發(fā)現(xiàn)NPM1可以結(jié)合至三陰性乳腺癌細(xì)胞的PD-L1轉(zhuǎn)錄起始位點(diǎn)DNA序列，并且激活PD-L1轉(zhuǎn)錄，從而抑制T淋巴細(xì)胞離體和在體活性。

　　此外，該研究還證實(shí)，多腺苷二磷酸核糖聚合酶PARP1通過與NPM1的PD-L1轉(zhuǎn)錄起始位點(diǎn)DNA序列核酸結(jié)合區(qū)發(fā)生相互作用，可以抑制PD-L1轉(zhuǎn)錄。PARP1抑制劑奧拉帕利可以提高三陰性乳腺癌的PD-L1表達(dá)水平，從而充分PD-L1抑制劑的療效。

　　因此，該研究結(jié)果表明，NPM1作為三陰性乳腺癌的PD-L1轉(zhuǎn)錄調(diào)節(jié)因子，有望成為新的治療靶點(diǎn)，有助于提高三陰性乳腺癌的免疫治療效果。

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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