title: Tumor-Promoting Effects of Myeloid-Derived Suppressor Cells Are Potentiated by Hypoxia-Induced Expression of miR-210.
abstract: Myeloid-derived suppressor cells (MDSC) contribute significantly to the malignant characters conferred by hypoxic tumor microenvironments. However, selective biomarkers of MDSC function in this critical setting have not been defined. Here, we report that miR-210 expression is elevated by hypoxia-inducible factor-1α (HIF1α) in MDSC localized to tumors, compared with splenic MDSC from tumor-bearing mice. In tumor MDSC, we determined that HIF1α was bound directly to a transcriptionally active hypoxia-response element in the miR-210 proximal promoter. miR-210 overexpression was sufficient to enhance MDSC-mediated T-cell suppression under normoxic conditions, while targeting hypoxia-induced miR-210 was sufficient to decrease MDSC function against T cells. Mechanistic investigations revealed that miR-210 modulated MDSC function by increasing arginase activity and nitric oxide production, without affecting reactive oxygen species, IL6, or IL10 production or expression of PD-L1. In splenic MDSC, miR-210 regulated Arg1, Cxcl12, and IL16 at the levels of both mRNA and protein, the reversal of which under normoxic conditions decreased T-cell-suppressive effects and IFNγ production. Interestingly, miR-210 overexpression or targeting IL16 or CXCL12 enhanced the immunosuppressive activity of MDSC in vivo, resulting in increased tumor growth. Taken together, these results provide a preclinical rationale to explore miR-210 inhibitory oligonucleotides as adjuvants to boost immunotherapeutic responses in cancer patients.
authors.affiliation: Unité INSERM U1186, Gustave Roussy, Villejuif, France.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health (CRP-Santé), Luxembourg City, Luxembourg.
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: Department of Medicine, Division of Cardiology, Stanford, California. Department of Radiology, Molecular Imaging Program, Stanford, California.
authors.forename: Shijun
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Medicine, Division of Cardiology, Stanford, California. Department of Radiology, Molecular Imaging Program, Stanford, California.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
authors.affiliation: VeronaUniversity, P. le L.A. Scuro 10, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Unité INSERM U1186, Gustave Roussy, Villejuif, France. chouaib@igr.fr.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D019410:Interleukin-16 / Q000096:biosynthesis / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology; D014158:Transcription, Genetic; D059016:Tumor Microenvironment
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019410:Interleukin-16; C549325:MIRN210 microRNA, mouse; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D009569:Nitric Oxide; C544448:Arg1 protein, mouse; D001119:Arginase