Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response

Abstract

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.

Targeted suppression of microRNA-33 in lesional macrophages using pH low-insertion peptides (pHLIP) improves atherosclerotic plaque regression

“…These ndings correlate with our previous studies showing a speci c uptake of pHLIP in tumor associated macrophages. 23 Similar to the results observed in vivo, acidi cation of the media (pH = 6.2) promoted a marked increase of A546-Var3 uptake in mouse macrophages compared to macrophages cultured at a neutral pH ( Fig. 2a).…”

Macrophage-derived miR-21 drives overwhelming glycolytic and inflammatory response during sepsis via repression of the PGE2/IL-10 axis

“…There is no common scientific consensus about the exact mechanism of miR-21 in the induction or repression of the inflammatory program. Several manuscripts suggest miR-21 as an anti-inflammatory target (41,(73)(74)(75), while others suggested this miRNA as a crucial proinflammatory factor (36,40,76). We observed an overall decrease in IL6 and IL1b and an increase in IL10 abundance in septic miR21∆myel when compared to septic WT mice.…”

<p>Downregulation of miR-7-5p Inhibits the Tumorigenesis of Esophagus Cancer via Targeting KLF4</p>

“…MiRNAs have been confirmed to play important roles in the occurrence of EC. [19][20][21] In this research, we found that the downregulation of miR-7-5p could notably suppress the growth of EC cells. Our study firstly explored the role of miR-7-5p in EC.…”