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Oncogene. 2018 Jun;37(23):3151-3165. doi: 10.1038/s41388-018-0178-3. Epub 2018 Mar 15.

miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy.

Author information

1
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
2
Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, China.
3
Raman Fellow (UGC), Department of Biochemistry, University of Allahabad, Allahabad, India.
4
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450000, China.
5
Cancer Research Institute, Central South University, Changsha, 410078, China.
6
Departments of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
7
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. liy2@ccf.org.

Abstract

MicroRNA-21 (miR-21) is one of the most abundant microRNAs in mammalian cells. It has been intensively studied for its role in regulating apoptosis and oncogenic transformation. However, the impact of miR-21 on host anti-tumor immunity remains unknown. Tumor-associated macrophages are a major leukocyte type that infiltrates tumors and predominantly develops into immunosuppressive, tumor-promoting M2-like macrophages. In contrast, the pro-inflammatory M1-like macrophages have tumoricidal activity. In this study, we show that genetic deficiency of miR-21 promotes the polarization of macrophages toward an M1-like phenotype in vivo and in vitro in the presence of tumor cells; thus it confers host mice with enhanced anti-tumor immunity. By downregulating JAK2 and STAT1, miR-21 inhibits the IFN-γ-induced STAT1 signaling pathway, which is required for macrophage M1 polarization. We also show that the expression of miR-21 in macrophages is regulated upon polarization stimuli as well as upon macrophages co-culturing with tumor cells. Thus, tumor cells may stimulate miR-21 expression in tumor-associated macrophages to prevent tumoricidal M1 polarization. However, augmented STAT1 signaling mediated by miR-21 deficiency upregulates PD-L1 expression in macrophages, which is known to inhibit phagocytic anti-tumor activity. This adverse effect can be alleviated by PD-1 blockade; indeed, miR-21 depletion in macrophages and PD-1 antibody treatment offer superior anti-tumor activity than either agent alone. These studies shed lights on potential application of the combination of miR-21 inhibition and immune checkpoint blockade to target the tumor microenvironment.

PMID:
29540832
PMCID:
PMC5993583
DOI:
10.1038/s41388-018-0178-3
[Indexed for MEDLINE]
Free PMC Article

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