Journal Article

NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer

Qin, Ge, Wang, Xin, Qin, Tao, Tang, Yanlai, Kang, Tiebang, Chen, Miao, Li, Yixin, Long, Qian, Zhang, Kai, Xie, Fangyun, Hu, Huabin, Li, Jiaping, Lan, Ping, Deng, Wuguo, Li, Yizhuo, Ye, Shubiao, Zhang, Changlin, Lu, Jianjun, Zhai, Qinglian, Shi, Dingbo, Wang, Shusen

2020

Overview

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. PD-L1 is highly expressed in triple-negative breast cancers (TNBC). Here, the authors show that nucleophosmin 1 (NPM1) transcriptionally activates PD-L1 expression and inhibits T cell activity in TNBC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/105 / 13/109 / 13/31 / 13/51 / 13/89 / 14/19 / 38/77 / 38/88 / 45/22 / 64/60 / 692/4028/67/1059/2325 / 692/4028/67/1347 / 82/29 / 82/58 / 82/83 / Adult / Aged / Animals / Antineoplastic Agents, Immunological - pharmacology / Antineoplastic Agents, Immunological - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Binding / Breast - pathology / Breast cancer / Cancer immunotherapy / Cell death / Cell Line, Tumor / Disease Models, Animal / DNA-Binding Proteins / Drug Synergism / Female / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - immunology / Gene Knockdown Techniques / Humanities and Social Sciences / Humans / Immunotherapy / Kaplan-Meier Estimate / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Mice / Middle Aged / multidisciplinary / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Nucleic acids / PD-1 protein / PD-L1 protein / Phthalazines - pharmacology / Phthalazines - therapeutic use / Piperazines - pharmacology / Piperazines - therapeutic use / Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Prognosis / Promoter Regions, Genetic - genetics / Science / Science (multidisciplinary) / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tissue Array Analysis / Transcription / Transcriptional Activation - immunology / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - immunology / Triple Negative Breast Neoplasms - mortality / Up-Regulation - drug effects