EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1

Jie Wang; Junshang Ge; Yian Wang; Fang Xiong; Jiayue Guo; Xianjie Jiang; Lishen Zhang; Xiangying Deng; Zhaojian Gong; Shanshan Zhang; Qijia Yan; Yi He; Xiayu Li; Lei Shi; Can Guo; Fuyan Wang; Zheng Li; Ming Zhou; Bo Xiang; Yong Li; Wei Xiong; Zhaoyang Zeng

doi:10.1038/s41467-022-28479-2

EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1

Nat Commun. 2022 Feb 14;13(1):866. doi: 10.1038/s41467-022-28479-2.

Authors

Jie Wang^{1

2}, Junshang Ge², Yian Wang², Fang Xiong³, Jiayue Guo², Xianjie Jiang², Lishen Zhang², Xiangying Deng², Zhaojian Gong⁴, Shanshan Zhang³, Qijia Yan³, Yi He¹, Xiayu Li⁵, Lei Shi^{2

4}, Can Guo², Fuyan Wang², Zheng Li², Ming Zhou², Bo Xiang², Yong Li⁶, Wei Xiong^{7

8}, Zhaoyang Zeng^{9

10}

Affiliations

¹ NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
² Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China.
³ Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁵ Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁶ Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁷ NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. [email protected].
⁸ Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China. [email protected].
⁹ NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. [email protected].
¹⁰ Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, Hunan, China. [email protected].

Abstract

Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126 ), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen / metabolism
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / metabolism
Epstein-Barr Virus Infections / virology
Forkhead Transcription Factors / antagonists & inhibitors
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic / genetics
Herpesvirus 4, Human / genetics*
Herpesvirus 4, Human / immunology
Humans
Lymphoma / immunology
Lymphoma / virology
MicroRNAs / genetics*
Nasopharyngeal Carcinoma / genetics
Nasopharyngeal Carcinoma / immunology*
Nasopharyngeal Carcinoma / virology
Nasopharyngeal Neoplasms / genetics
Nasopharyngeal Neoplasms / immunology*
Nasopharyngeal Neoplasms / virology
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / metabolism
Stomach Neoplasms / immunology*
Stomach Neoplasms / virology
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism
Tumor Escape / genetics
Tumor Escape / immunology*
Tumor Microenvironment / immunology

Substances

B7-H1 Antigen
CD274 protein, human
DNA-Binding Proteins
FOXP1 protein, human
Forkhead Transcription Factors
MicroRNAs
Mir-BART11, Epstein-Barr virus
PBRM1 protein, human
Repressor Proteins
Transcription Factors