Back to Search Start Over

miRNA-5119 regulates immune checkpoints in dendritic cells to enhance breast cancer immunotherapy

Authors :
Qing Li
Fang-Fang Dou
Dian Gao
Faizah Alotaibi
Hongmei Wang
Wei-Ping Min
Zhigang Wang
James Koropatnick
Yanling Liu
Meng Zhang
Yanmei Shi
Yujuan Zhang
Yifan Wang
Li Qiu
Shanshan Peng
Keng Yuan
Jianping Xiong
Source :
Cancer immunology, immunotherapy : CII. 69(6)
Publication Year :
2019

Abstract

Dendritic cell (DC) based immunotherapy is a promising approach to clinical cancer treatment. miRNAs are a class of small non-coding RNA molecules that bind to RNAs to mediate multiple events which are important in diverse biological processes. miRNA mimics and antagomirs may be potent agents to enhance DC-based immunotherapy against cancers. miRNA array analysis was used to identify a representative miR-5119 potentially regulating PD-L1 in DCs. We evaluated levels of ligands of immune cell inhibitory receptors (IRs) and miR-5119 in DCs from immunocompetent mouse breast tumor-bearing mice, and examined the molecular targets of miR-5119. We report that miRNA-5119 was downregulated in spleen DCs from mouse breast cancer-bearing mice. In silico analysis and qPCR data showed that miRNA-5119 targeted mRNAs encoding multiple negative immune regulatory molecules, including ligands of IRs such as PD-L1 and IDO2. DCs engineered to express a miR-5119 mimic downregulated PD-L1 and prevented T cell exhaustion in mice with breast cancer homografts. Moreover, miR-5119 mimic-engineered DCs effectively restored function to exhausted CD8+ T cells in vitro and in vivo, resulting in robust anti-tumor cell immune response, upregulated cytokine production, reduced T cell apoptosis, and exhaustion. Treatment of 4T1 breast tumor-bearing mice with miR-5119 mimic-engineered DC vaccine reduced T cell exhaustion and suppressed mouse breast tumor homograft growth. This study provides evidence supporting a novel therapeutic approach using miRNA-5119 mimic-engineered DC vaccines to regulate inhibitory receptors and enhance anti-tumor immune response in a mouse model of breast cancer. miRNA/DC-based immunotherapy has potential for advancement to the clinic as a new strategy for DC-based anti-breast cancer immunotherapy.

Details

ISSN :
14320851
Volume :
69
Issue :
6
Database :
OpenAIRE
Journal :
Cancer immunology, immunotherapy : CII
Accession number :
edsair.doi.dedup.....d31433461b928327ef5f6705aba66bee