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.
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Acknowledgements
We are grateful to Dr. Cassandra Talerico for editing the manuscript and providing critical comments.
Author contributions
J.X., Q.H., L.W., and Y.L. designed the research and performed experiments. All authors contributed to research and data analyses. J.X., Q.H., L.W., and Y.L. wrote the manuscript, and all authors approved the final version of the manuscript.
Funding
This study is supported by NIH R01 grants (CA138688 and CA177810) and Natural Science Foundation of China (No. 81528019).
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Xi, J., Huang, Q., Wang, L. et al. miR-21 depletion in macrophages promotes tumoricidal polarization and enhances PD-1 immunotherapy. Oncogene 37, 3151–3165 (2018). https://doi.org/10.1038/s41388-018-0178-3
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DOI: https://doi.org/10.1038/s41388-018-0178-3