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Theranostics 2021; 11(3):1412-1428. doi:10.7150/thno.53092 This issue Cite

Research Paper

Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

Xin Lai^1,5,6✉, Florian S. Dreyer^1,5,6, Martina Cantone^1,5,6, Martin Eberhardt^1,5,6, Kerstin F. Gerer^2,5,6, Tanushree Jaitly^1,5,6, Steffen Uebe³, Christopher Lischer^1,5,6, Arif Ekici³, Jürgen Wittmann⁴, Hans-Martin Jäck⁴, Niels Schaft^2,5,6, Jan Dörrie^2,5,6, Julio Vera^1,5,6✉

1. Laboratory of Systems Tumor Immunology, Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
2. RNA Group, Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
3. Department of Human Genetics, Universitätsklinikum Erlangen, Erlangen, Germany.
4. Division of Molecular Immunology, Department of Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
5. Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
6. Comprehensive Cancer Center (CCC) Erlangen, Erlangen, Germany.

✉ Corresponding authors: Xin Lai, Tel: +49(0)91318545888, E-mail: xin.laide; Julio Vera, Tel: +49(0)91318545876, E-mail: julio.vera-gonzalezde.

Abstract

Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs).

Methods: Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses.

Results: Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates, with miR-15a and miR-16 as the top ones. The results of our analysis are presented in a database that constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (https://www.synmirapy.net/dc-optimization).

Conclusions: Our approach enables the systematic analysis and identification of functional miRNA-gene interactions that can be experimentally tested for improving DC immunogenic potency.

Keywords: dendritic cell, therapeutic vaccination in cancer, systems biology, network biology, microRNAs

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