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miRNA-5119 regulates immune checkpoints in dendritic cells to enhance breast cancer immunotherapy
- 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.
- Subjects :
- Cancer Research
medicine.medical_treatment
T cell
Immunology
Breast Neoplasms
Biology
Transfection
Cancer Vaccines
03 medical and health sciences
Mice
0302 clinical medicine
Immune system
Cancer immunotherapy
Cell Line, Tumor
microRNA
medicine
Immunology and Allergy
Animals
Humans
Immunotherapy
Dendritic cell
Dendritic Cells
Disease Models, Animal
MicroRNAs
Cytokine
medicine.anatomical_structure
Oncology
Cancer research
Female
CD8
030215 immunology
Subjects
Details
- ISSN :
- 14320851
- Volume :
- 69
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Cancer immunology, immunotherapy : CII
- Accession number :
- edsair.doi.dedup.....d31433461b928327ef5f6705aba66bee