MiR-29b antagonizes the pro-inflammatory tumor-promoting activity of multiple myeloma-educated dendritic cells

Cirino Botta ,Rao Prabhala ,Emanuela Altomare ,Lavinia Biamonte ,Maria Teresa Di Martino ,Nicola Amodio ,Chiara Mignogna ,Caterina Riillo ,Maria Rita Pitari ,Marco Rossi ,Eugenio Morelli ,Daniele Caracciolo ,Maria Eugenia Gallo Cantafio ,Pierosandro Tagliaferri ,Pierpaolo Correale ,Nikhil C Munshi ,Antonio Giordano ,Anna Di Vito ,Annamaria Gullà ,Maria Cucè ,Pierfrancesco Tassone

doi:10.1038/leu.2017.336

Abstract

Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-κB, and cytokine/chemokine signaling networks, which correlated with patients’ adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM.

Highlights

Multiple myeloma (MM) is an incurable malignancy characterized by uncontrolled clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM)
We observed that miR-29b was upregulated during dendritic cell (DC) differentiation from monocyte precursors (Supplementary Figure 1A) and after maturation with lipopolysaccharide or co-culture with allogenic lymphocytes (Figure 1b), whereas it was significantly downregulated in DCs after co-culture with all MM cell lines (Figure 1b)
To validate our observation in MM patient-derived DCs, we investigated miR-29b expression in CD11c+/CD45+ DCs retrieved from BM of six MM patients and five healthy donor (HD) (Figure 1c)

Summary

Introduction

Multiple myeloma (MM) is an incurable malignancy characterized by uncontrolled clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM).

Results

Conclusion