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International Journal of Molecular Sciences
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11 March 2013

MicroRNAs Involved in Anti-Tumour Immunity

,
and
1
Department of Health Technology and Informatics, the Hong Kong Polytechnic University, Hong Kong, China
2
Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci.2013, 14(3), 5587-5607;https://doi.org/10.3390/ijms14035587
This article belongs to the Special Issue Advances in Molecular Oncology (special issue)
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Abstract

MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity.

1. Introduction

MicroRNAs (miRNAs) are a group of small non-coding RNA molecules that play a central role in a number of biological processes through the post-transcriptional regulation of gene expression. This class of molecules provides the relevant regulation epigenetically in addition to the major categories of DNA methylation, histone deacetylation, chromatin remodelling, gene imprinting, and noncoding RNA regulation [1].
miRNAs have been shown to be critical contributors in the pathogenesis of many diseases including cancer. On one hand, miRNAs present as potential future diagnostic and prognostic markers and as viable therapeutic targets for cancer treatment [2–4]. On the other hand, miRNAs are also important regulators of the development and functions of diverse immunologically important cell types and the related complex cytokine network.
There are two major arms of the immune system, known as the innate and adaptive immune responses, which work in a complementary manner to help the body maintain its healthy status. The major players of the innate immune system that provide the first line of defence are natural killer (NK) cells, γδ T cells and macrophages. These cells, together with some inflammatory cytokines, critically defend the barriers at the mucosal and cutaneous levels. In the adaptive immune system, specificity and memory are the two key characteristics that are absent in the innate immune system. Dendritic cells (DC), B cells and T cells are the three cooperating major cell types that constitute the adaptive immune system.
Some lineage-specific miRNAs have been found to play a key role in regulating various developmental stages of the lineage development of the two major arms and thus affect different cell types in the mature state and their progenitor counterparts [5]. miRNAs are also involved in the activation of various immune cell components and thus regulate various cancer-related inflammatory responses and cytokine signalling [6,7]. Furthermore, certain miRNAs display the important modulatory capabilities on the life span, migration and immunogenicity of immune cells. For example, research showing that harnessing these features of miRNA targeting of DCs may lead to possible DC vaccine development for future clinical trials [8]. Figure 1 forms a visible representation of the involved miRNAs in immune cells.
Figure 1. Involvement of miRNAs in immune cells.

2. miRNAs and Innate Immunity

One of the important cell types for the first line of defence of the immune system is the epithelial cell population that expresses some pathogen pattern recognition receptors, including the Toll-like receptors (TLRs), which recognise pathogen-associated molecular patterns and can induce strong pro-inflammatory responses [9]. In the recognition of pathogens, TLRs recruit adaptor proteins to facilitate the activation of downstream signalling cascades, such as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase pathways. The activation process induces the expression of adhesion molecules, inflammatory mediators of cytokines or chemokines, and antimicrobial peptides that initiate innate immune responses and anti-tumour involvement, which are regulated by a number of complex networks. miRNAs are the essential portion of these complex regulatory networks for the cellular processes, differentiation and final fate of these innate immune cells [10].
Another major cell population of the innate immune response is the macrophages. Tissue macrophages detect pathogens through TLRs and after phagocytosing these pathogens, initiate the innate immune responses [11]. Macrophages, in response to microbes, produce cytokines that stimulate inflammation via leukocyte recruitment. Subsequently, NK cells are activated and produce the macrophage-activating cytokine IFN-γ, which is now known to have a central role in the regulation of inflammation. Additionally, miR-19 has been found to be involved in modulating this NF-κB-based inflammatory activity [12]. Table 1 provides a summary of a list of miRNAs and their corresponding target genes in the activation of macrophages and NK cells.
Table 1. miRNAs involved in innate immunity.

2.1. Macrophages

Macrophage subsets include the ‘classically activated’ pro-inflammatory (M1) and ‘alternatively activated’ anti-inflammatory (M2) cells [23]. The transcriptional activation of macrophage mannose receptor 1 (MRC1) in M2-polarised tumour-associated macrophages (TAMs) involves miR-511-3p regulation to establish the threshold for inflammatory cell activation in tumours in which the induced expression of miR-511-3p downregulates the pro-tumour gene signature of MRC1(+) TAMs and inhibits tumour growth [13]. The transcription of the miR-146a gene in human THP-1 cells has been reported in response to TLR-4 signalling, and miR-146a acts on the target genes TNF-receptor associated factor 6 (TRAF6) and IL-1 receptor associated kinase 1 (IRAK1) through the NF-κB-dependent cascade [14]. Similarly, miR-27b expression can also be induced directly by lipopolysaccharide (LPS) [15]. In addition, LPS will regulate miR-9 expression via the myeloid differentiation primary response gene 88 through the NF-κB pathway in human macrophages and neutrophils [16].
miRNAs, such as miR-222 and miR-339, have also been implicated in the expression of adhesion and costimulatory molecules, including the intercellular adhesion molecule 1 (ICAM1), which is essential in the interactions of innate immune cells [17]. miR-125b has also been reported to regulate the expression of cytokines and chemokines by targeting and suppressing tumour necrosis factor α (TNF-α) transcription in mouse Raw 264.7 macrophages [18]. Furthermore, miR-16 has been demonstrated to be one of the critical regulators of inflammatory responses, with a high level of miR-16 in inflammatory cells that inhibit the production of inflammatory mediators [19].

2.2. NK Cells

NK cells are essential innate immune components with potent cytotoxicity and type I IFN (INF-α) initiation capability. Wang et al.[20] reported that the expression of miR-378 and miR-30e is markedly decreased in IFN-α-activated NK cells that are labelled as granzyme B (GZMB)- and perforin (PRF)-positive. In contrast, downregulated miR-378 and miR-30e are the negative regulators of NK cell cytotoxicity during activation in the subset of sorted CD16(+)CD56(dim)CD69(+) human NK cells.
Another important cytokine produced by NK cells is TNF-α. The up-regulation of miR-30c-1* is now known to trigger the overexpression of transmembrane TNF-α, which in turn enhances NK cell cytotoxicity against the hepatoma cell lines SMMC-7721 and HepG2 by targeting the transcriptional repressor gene HMBOX1 [22,24]. In contrast, miR-27a* is able to negatively regulate NK cell cytotoxicity by silencing the genes PRF1 and GZMB, as shown by the knockdown of miR-27a* in NK cells, which leads to decreased tumour growth in a human tumour xenograft model [21].

3. miRNAs and Adaptive Immunity

miRNAs play an important role in the early differentiation of B cells and act as regulators of the immune response by T cells and DCs in adaptive immunity. Great efforts have been made to demonstrate the role of miRNAs in adaptive immune cells in recent years. Table 2 summarises the miRNAs involved in adaptive immunity and their respective target genes, with the third column showing those miRNAs participating in these cell types at various developmental stages.
Table 2. miRNAs involved in adaptive immunity.

3.1. B Cells

The expression of the transcription factors for B-cell development has been found to be precise and time-specific under the influence of a few miRNAs on B cells at various maturation stages. It is evident that the alteration of miRNA expression may lead to important functions in cellular differentiation and be associated with the activation status of the mature B cells in the immune system [49]. The role of miRNAs in B-cell development and B-cell lymphogenesis is largely unknown. The stage-specific expression of various miRNAs has suggested highly specialised regulatory functions in B-cell biology, which would reveal the cell type-specificity of miRNAs in B lymphocytes [50].
The expression of miR-150 was shown to block the transition from the pro-B to pre-B stage, likely through the down-regulation of c-MYB [28–30]. miR-17~92 is also essential for B-cell development, in which the absence of miR-17~92 will lead to the elevated expression of the pro-apoptotic protein BIM, which in turn inhibits B-cell development at the pro-B to pre-B transition. A link between the oncogenic properties of miR-17~92 and its physiological functions during B lymphopoiesis has been suggested [26]. Accordingly, B-cell development could be partially rescued by the ablation of BIM through the suppression of miR-17~92 [27]. In addition to miR-150 and miR-17~92, miR-34a was also found to block B-cell development at the transition from pro-B to pre-B cells via the target gene forkhead box transcription factor (FOXP1), which is a transcription factor gene; this process leads to a reduction in mature B cells. Accordingly, the knockdown of miR-34a resulted in the elevation of FOXP1 expression and an increase in mature B cells [25].
The association of miR-155 with the primary transcript of the host gene BIC was observed in preleukaemic pre–B-cell proliferation in the spleen and bone marrow of transgenic mice [31,32]. The high expression of miR-155 was also observed in murine B-cell precursors of acute lymphoblastic leukaemia or high-grade lymphoma, which were preceded by polyclonal pre-B cell proliferation. miR-155 directly targeted SRC homology 2 domain-containing inositol-5-phosphatase (SHIP) and CCAAT enhancer-binding protein beta (C/EBPβ), which are both regulators of the IL-6 signalling pathway. miR-155 was hypothesised to cause accumulation of large pre-B cells and acute lymphoblastic leukaemia by down-regulating SHIP and C/EBPβ [33].
The over-expression of miR-21 has been found in a number of tumour types. Medina et al.[51] demonstrated that the over-expression of miR-21 leads to a pre-B malignant lymphoid-like phenotype and that the tumours regressed completely in a few days after miR-21 was inactivated. miR-125b has been found to up-regulate a number of common myeloid progenitors and to inhibit the development of pre-B cells by acting on some candidate targets, including the induced pluripotent stem cell gene LIN28A [34]. miR-125b physiologically regulates haematopoietic development. LIN28A was saliently suppressed in mouse haematopoietic stem cells and progenitor cells, and the knockdown of LIN28A can lead to haematopoietic lineage skewing with an increase in myeloid cells but decrease in B cells.
The deregulation of miR-181a, miR-181b, miR-107 and miR-424 was found to lead to the subsequent overexpression of the oncogenic transcription factor pleomorphic adenoma gene 1 (PLAG1) in a number of chronic lymphocytic leukaemia (CLL) cases [36,37]. CLL is characterised by the clonal expansion of immature CD5-positive B cells; up to 20 percent of the patients with CLL are not controlled with standard therapies using cytotoxic agents. The 13q14.3 chromosomal region often found in patients with CLL contains miR-15a and miR-16-1 [35]. Tan et al.[38] characterised the miRNA expression profile of normal B cell subsets that included naïve, germinal centre (GC) B cells and memory B cells with a miRNA in situ hybridisation technique. Several miRNAs were elevated in GC B cells, such as miR-17-5p, miR-106a and miR-181b, whereas the gradual decrease in the staining intensity of these three miRNAs from the dark to light zone was observed in GC. miR-150 was the most abundant in all three B-cell subsets.
In a study of the expression of a panel of 15 miRNAs in some DLBCL cases, the expression of miR-17-5p was significantly higher in central nervous system diffuse large B cell lymphoma (DLBCL) than in testicular DLBCL, and miR-127 was found to be highly expressed in testicular DLBCL compared with central nervous system DLBCL [39].
Iqbal et al.[40] identified a 19-miRNA classifier including 6 up-regulated miRNAs and 13 down-regulated miRNAs that helped distinguish mantle cell lymphoma (MCL) from other aggressive lymphomas, and some of the up-regulated miRNAs were highly expressed in naïve B cells. The high expression of miR-17~92, miR-106a-363 and miR-106b-25 was observed in some patients with MCL in their studies. For example, miR-155 is encoded in the B cell integration cluster, and its knockdown leads to B cell defects and a failure of immunoglobulin-switched plasma cells. The transcription factor PU.1 is the validated target of miR-155 [41].

Related Signalling Pathways in Lymphoma

The PI3K/PTEN/AKT pathway is one of the key signalling pathways involved in the regulation of cell growth. The frequent dysregulation of the PI3K/PTEN pathway in human cancer demonstrates that this pathway is an appropriate target for cancer therapeutics [52]. Hafsi et al.[53] suggested that the dysregulated signalling of this pathway might be associated with activating mutations in PI3K-related genes. An increased PI3K signal will stimulate downstream AKT signalling, promote growth factor-independent growth and facilitate cell invasion and metastasis, which account for 50% of all human malignancies [54]. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain or amplification, which targets the miR-17~92 cluster. Rao et al.[55] demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17~92 which also targeted PTEN and BIM. The inhibition of miR-17~92 suppressed the PI3K/AKT pathway, which in turn inhibited tumour growth in the xenograft MCL mouse model. Hence, targeting the miR-17~92 cluster may provide a novel therapeutic approach for patients with MCL.

3.2. T Cells

miRNAs have been shown to be involved in the regulation of T-cell responses, with a dynamic expression pattern relative to the various stages of T cell development. miR-135b was reported to mediate nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and induce the immunophenotype of IL-17 in anaplastic large cell lymphoma (ALCL). Oncogene NPM-ALK strongly promoted miR-135b expression through the activation of transducer and activator of transcription (STAT) 3, and the elevated miR-135b targets FOXO1, a transcription factor regulating gluconeogenesis and glyconeogensis via insulin signalling in ALCL cells. Chemosensitivity in Jurkat cell line was found to be decreased by miR-135b [42]. Furthermore, miR-135b suppresses the T-helper 2 regulator gene STAT6 and GATA3, whereas antisense-based miR-135b inhibition induces tumour angiogenesis in vivo.
NKG2D, encoded by the KLRK1 gene, is one of the activating immunoreceptors found on CD8 T cells and NK cells, and its ligands are stress-inducible proteins, including ULBP1, that enable the recognition and lysis of tumour cells. Some miRNAs were shown to be involved in the post-transcriptional regulation of ULBP1 expression in Jurkat and HeLa cells. Among these miRNAs, miR-140-5p, miR-409-3p, miR-433-3p and miR-650 are involved in the regulation of ULBP1 expression [43].

3.3. Dendritic Cells

DCs are found in almost all peripheral tissues and in primary and secondary lymphoid organs. The antigen presentation of DC controls immunity and tolerance, is linked with almost all types of immune cells and plays major roles in regulation of immune responses [56].
Cubillos-Ruiz et al.[44] took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated DCs to selectively supplement the immunostimulatory miR-155. Modulating the activity of miRNAs may lead to cancer interventions. miR-155 that has been processed endogenously would favour Argonaute 2 (AGO2) and AGO4 loading, resulting in transcriptional changes that might silence multiple immunosuppressive mediators [57]. Thus, tumour-infiltrating DCs were transformed into highly immunostimulatory cells, triggering potent anti-tumour responses to abrogate the progression of ovarian cancer.
Concerning the tolerogenic property of DCs, miR-23b may be one of the entry points in targeting the therapeutic management of allergies. The upregulation of miR-23b could be observed in bone marrow DCs (BMDCs) by ovalbumin in a murine model. Increased IL-10 levels, decreased IL-12 levels and an enhancement of the FOXP3+ CD4+ T regulatory cell differentiation were shown in BMDCs by the transfection of miR-23b, likely through the inhibition of the transmembrane protein family member NOTCH1 and the NF-κB signalling pathway [45]. Similar results were also obtained in human monocyte-derived DCs.
Some miRNAs, such as miR-146a and miR-155, may act as checkpoints in the cellular differentiation aspect of the immune system [46]. Using a miRNA array, Holmstrom et al.[8] demonstrated a significant induction of miR-155, miR-146a and miR-125a-5p in some donor DCs treated with LPS. In addition to miR-146a and miR-155, miR-132 is a TLR ligand-induced regulator of inflammatory mediators, which may modulate TLR pathway activation and may be used to develop relevant therapeutics for inflammatory diseases [47]. miR-511 has been identified as a novel potent modulator of the human immune response through the validation of CD80 expression and inhibition of miR-511 in HEK293 cells. Similarly, DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) was found to be reduced, thereby revealing that miR-511 may act as a positive regulator of TLR-4 [48].

5. Discussion

Emerging evidence has shown that miRNAs are important modulators in cancer pathogenesis within the bigger picture of how cells are transformed into malignant cells and multiply in an uncontrolled manner, followed by tissue invasion and metastasis. Equally, research has also indicated that miRNAs can be effective inhibitors as anti-tumour agents. In this regard, an example such as the antisense-based inhibition of a specific miRNA has been found to be useful due to the enhancement of the corresponding anti-tumour immunity [18].
The development of plasma-circulating miRNA detection and expression profiles, which have been found in association with a range of tumour types, can also be used in therapeutic strategies [103,106] and in various clinical settings of cancer management [107]. As shown in Table 3, a variety of miRNAs are either up-regulated or down-regulated in different tumour types. Examples include the following: oesophageal squamous cell carcinoma identified with the elevated expression of miR-21, miR-25, miR-92, and miR-142-3p; gastric cancer with the down-regulated expression of miR-155, miR-148a, miR-182 and miR-409-3p; and hepatic cellular cancer with the up-regulated expression of miR-124, miR-199a, miR-373 and miR-519d.

6. Current Studies Targeting miRNAs for Therapeutic Purposes

Mechanisms of resistance in anticancer treatment have been postulated to be associated with the altered expression of the ATP-binding cassette family of transporters involved in cell membrane transportation. Thus, the emerging role of miRNAs as key gene expression regulators in drug resistance can be the specific mechanism involved in combating the resistance to tyrosine kinase inhibitors in chronic myeloid leukaemia [108]. An understanding of how the involved miRNAs influence the phosphatidylinositol 3 kinase PI3K/AKT signalling pathway in modulating the function of the breast cancer-resistant protein can lead to a therapeutic benefit in breast cancer [109,110].
Techniques that restore the activity of tumour suppressor miRNAs by the inhibition of oncogenic miRNAs using single-stranded antisense oligonucleotides or antimiR have been recently employed for the development of miRNA-based cancer therapeutics [111–113]. In recent studies, certain cancers exhibited dependence on the expression of a single oncogenic miRNA or oncomir [114]. The possible programming of the balance between the expression of oncogenic miRNAs and tumour suppressor miRNAs may result in the specific anti-tumour effect [97].
To target miRNAs in cancer, one strategy involves hindering the oncomir from expression or rebuilding the corresponding tumour suppressor miRNA that might have lost in the cancer. The apoptosis of leukaemic MEG01 could be induced through the reintroduction of miR-15a and miR-16-1, which were shown to inhibit tumour growth in vivo in a xenograft model [115], and silencing the oncogenic miR-21 via antisense oligonucleotides has generated an anti-proliferative response in vitro in a number of cellular models [116]. Although chemically modified anti-miRNA oligonucleotides have been developed [117,118], nevertheless, their effective delivery into target tissues remains a limitation and needs to be further evaluated for a more specific delivery method with fewer side effects. In addition, the modulation of the miRNA expression via drugs or other agents during their transcription might show the potential of miRNAs as therapeutic adjuvant tools to improve the response and overcome resistance [119].

7. Future Challenges

The quantification of extracellular miRNAs in the blood circulation of both healthy and diseased patients was discovered to be confined to the lipid or lipoprotein complexes, such as microvesicles, exosomes or apoptotic bodies, which were highly stable [120]. These circulating miRNAs in cancer patients may serve as a novel diagnostic marker, although their logistic mechanism and the meaning of the quantified signatories of these extracellular miRNAs remain unclear. Hopefully, such identified molecular markers for the prediction of treatment outcome will be very useful, with the expression of circulating miRNAs being used to determine the clinical outcome in cancer patients treated with adjuvant chemotherapy [69].
Different studies have reported conflicting findings or inconsistencies regarding miRNAs from the same tumour, as shown in Table 3; for example, miR-519d has been found to be up-regulated in HCC [88] but down-regulated in a HCC cell line [92]. These findings show that there is a strong need to establish endogenous miRNA controls for normalisation in various methodologies during extraction and quantification. Furthermore, designing a well-planned and controlled analysis of miRNAs in a large cohort of both patients and healthy subjects may be necessary to provide more meaningful evidence for the quantification of miRNA expression and an insightful understanding concerning immunity and tumour biology. Such a trial will eventually lead to clinical advancements in cancer therapy and the significant enhancement of the management of various malignancies.

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