A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice

Zonari, Erika; Pucci, Ferdinando; Saini, Massimo; Mazzieri, Roberta; Politi, Letterio S.; Gentner, Bernhard; Naldini, Luigi

doi:10.1182/blood-2012-08-449306

Cited by 105 publications

(99 citation statements)

References 50 publications

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“…Several miRNAs have been implicated in the regulation of macrophage activation and polarization 23,57-59 ; however, only a few have been studied in the context of cancer 9,[24][25][26]60 . Bioinformatics modelling of the transcriptional profiles of D −/− and D +/+ TAMs identified the Let-7-5p-family miRNAs as candidate negative regulators of M1 TAM activation.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports have also begun to unravel the properties of individual miRNAs in TAMs. For example, miR-511-3p, miR-155-5p and miR-142-3p were all shown to limit M2-like macrophage activation in tumours 9,[24][25][26] . In this study, we genetically inactivated DICER in macrophages to analyse the effects of broadly disrupting miRNA activity on the immunoregulatory functions of TAMs.…”

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confidence: 97%

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Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity

et al. 2016

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Tumour-associated macrophages (TAMs) largely express an alternatively activated (or M2) phenotype, which entails immunosuppressive and tumour-promoting capabilities. Reprogramming TAMs towards a classically activated (M1) phenotype may thwart tumour-associated immunosuppression and unleash anti-tumour immunity. Here we show that conditional deletion of the microRNA (miRNA)-processing enzyme DICER in macrophages prompts M1-like TAM programming, characterized by hyperactive IFN-γ/STAT1 signalling. This rewiring abated the immunosuppressive capacity of TAMs and fostered the recruitment of activated cytotoxic T lymphocytes (CTLs) to the tumours. CTL-derived IFN-γ exacerbated M1 polarization of Dicer1-deficient TAMs and inhibited tumour growth. Remarkably, DICER deficiency in TAMs negated the anti-tumoral effects of macrophage depletion by anti-CSF1R antibodies, and enabled complete tumour eradication by PD1 checkpoint blockade or CD40 agonistic antibodies. Finally, genetic rescue of Let-7 miRNA activity in Dicer1-deficient TAMs partly restored their M2-like phenotype and decreased tumour-infiltrating CTLs. These findings suggest that DICER/Let-7 activity opposes IFN-γ-induced, immunostimulatory M1-like TAM activation, with potential therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

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confidence: 97%

Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity

et al. 2016

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“…They also found that miR-155 reveals antitumoral effect by acting as an integral effector of immunosurveillance, thereby inhibiting the early stages of breast cancer development. 115 On the other hand, programmed cell-death protein 1 and programmed cell death 1 ligand 1 (PD-1/PD-L1) eliminate T-cell activation in various forms of cancer. 116 The prospective trials to evaluate the efficacy of antibodies to PD-1/PD-L1 are undergoing in patients with TNBC.…”

Section: Mirna In Triple-negative Breast Cancermentioning

confidence: 99%

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

et al. 2016

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MicroRNAs (miRNAs) are short non-coding RNAs that regulate the function of target genes at the post-transcriptional phase. miRNAs are considered to have roles in the development, progression and metastasis of cancer. Recent studies have indicated that particular miRNA signatures are correlated with tumor aggressiveness, response to drug therapy and patient outcome in breast cancer. On the other hand, in routine clinical practice, the treatment regimens for breast cancer are determined based on the intrinsic subtype of the primary tumor. Previous studies have shown that miRNA expression profiles of each intrinsic subtypes of breast cancer differ. In hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, miRNA expressions are found to be correlated with endocrine therapy resistance, progesterone receptor expression and heat shock protein activity. Some miRNAs are associated with resistance to HER2-targeted therapy and HER3 expression in HER2-positive breast cancer. In triple-negative breast cancer, miRNA expressions are found to be associated with BRCA mutations, immune system, epithelial-mesenchymal transition, cancer stem cell properties and androgen receptor expression. As it has been clarified that the expression levels and functions of miRNA differ among the various subtypes of breast cancer, and it is necessary to take account of the characteristics of each breast cancer subtype during research into the roles of miRNA in breast cancer. In addition, the discovery of the roles played by miRNAs in breast cancer might provide new opportunities for the development of novel strategies for diagnosing and treating breast cancer.

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“…miR-155 is one such microRNAs that is considered to play a critical role in promoting macrophage polarization to the M1 phenotype [22]. Similarly TAM's, which overexpress miR-155, have significantly decreased tumor cell survival, promote tumor cell apoptosis and inhibit tumor cell invasion [23]. Thus miR-based re-polarization of macrophages provides a novel strategy for macrophage mediated cancer therapy.…”

Section: Discussionmentioning

confidence: 98%

Macrophage Polarization and the Effect of MicroRNA-155 Administered in Water-in-Oil-in-Water Multiple Emulsion Formulations

Oka¹,

Talekar²,

Ouyang³

et al. 2015

J Clin Cell Immunol

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The tumor microenvironment is composed of range of cells including macrophages that participate in sustaining tumor growth and invasion. Tumor-associated macrophages (TAM's) polarized to the M2 or pro-tumoral phenotype are one such population of cells highly expressed in the tumor microenvironment. The expression of microRNA's (miR's) is often found to be dysregulated in TAM's and hence exogenous delivery of miR provides a strategy for macrophage phenotypic modulation to attain improved anticancer activity. In this study, we assessed the use of multiple emulsions for the delivery of miR to achieve macrophage M1 repolarization. Water-in-oil-in-water (WOW) multiple emulsions (ME) were prepared using a two-step emulsification technique for encapsulation of miR-155 and cellular uptake, transfection efficiency, and repolarization capability of J774A.1 macrophages was assessed. The repolarized macrophages were co-cultured with SKOV3 ovarian cancer cells to assess the effect on macrophage morphology, motility and apoptosis of cancer cells. The ME showed enhanced uptake and expression of miR-155, which resulted in improved M1 polarization of J774A.1 cells. Co-culture studies with SKOV3 cells indicated an alteration in apoptotic profile. Holographic assessment of the co-cultured cells in real-time showed differences in motility and morphology of macrophages with miR-155 ME treated cells showing greater cellular interaction between the two phenotypes.

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A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice

Abstract: Key Points miR-155 knockdown in myeloid cells accelerates spontaneous breast cancer development. miR-155 is required by TAMs for deploying antitumoral activity.

Cited by 105 publications

References 50 publications

Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity

Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

Macrophage Polarization and the Effect of MicroRNA-155 Administered in Water-in-Oil-in-Water Multiple Emulsion Formulations

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