The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

// Michele Cioffi 1 , Sara M. Trabulo 1, 2 , Mireia Vallespinos 1 , Deepak Raj 2 , Tony Bou Kheir 2 , Meng-Lay Lin 2 , Julfa Begum 2 , Ann-Marie Baker 3 , Ala Amgheib 2 , Jaimy Saif 4 , Manuel Perez 5 , Joaquim Soriano 5 , Manuel Desco 6, 7, 8 , Maria Victoria Gomez-Gaviro 6, 7, 8 , Lorena Cusso 6, 7, 8 , Diego Megias 5 , Alexandra Aicher 1, 2 , Christopher Heeschen 1, 2 1 Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 2 Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK 3 Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK 4 School of Clinical Sciences, University of Bristol, Bristol, UK 5 Confocal Microscopy Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain 6 Departamento de Ingenieria Biomedica e Ingenieria Aeroespacial, Universidad Carlos III de Madrid, Leganes, Spain 7 Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Spain 8 Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Madrid, Spain Correspondence to: Alexandra Aicher, email: aicher_a@yahoo.com Christopher Heeschen, email: c.heeschen@qmul.ac.uk Keywords: metastasis, CD274, bone marrow, stromal niche, MDSC Received: June 29, 2016     Accepted: January 10, 2017     Published: February 17, 2017 ABSTRACT The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.