MicroRNAs as modulators of T cell functions in cancer

Highlights

• MicroRNAs are critical regulators able to shape T cell functions.

• Altered microRNA expression can cause oncogenic transformation of T cells.

• Altered expression of miRNAs can also influence T cell responses to cancer cells.

• Further functional studies will clarify the molecular details of miRNA functions.

Abstract

MicroRNAs (miRNAs) are short RNA molecules that regulate gene expression post-transcriptionally. They have emerged as important modulators of T lymphocyte biology, influencing cell activation, differentiation and proliferation in response to environmental signals. Here, we will discuss how miRNAs expressed by T cells can influence two key aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic transformation of T lymphocytes, as well as the indirect effects on tumor growth mediated by altered immune surveillance. We will specifically focus on three miRNAs that have been shown to regulate different aspects of T cell biology in both physiological and pathological conditions, namely miR-155, miR-146a and miR-181a. We aim at providing examples of the fundamental importance of miRNA-regulated networks in determining the fate of T lymphocytes during oncogenic transformation and in the control of tumor growth.

Introduction

T lymphocytes are central players in cell-mediated immunity, and they can be classified into two major subsets: CD4⁺ T helper (T_H) lymphocytes modulate the quality and magnitude of immune responses through the release of cytokines, secreted proteins able to influence cellular functions related to antimicrobial responses; CD8⁺ T cytotoxic lymphocytes are instead endowed with the ability to directly recognize and kill infected or transformed cells [1]. Despite the central role of T lymphocytes in protecting our organism from invading pathogens, their activity must be carefully regulated to avoid excessive tissue damage, altered inflammatory and anti-tumoral responses or even oncogenic transformation. At a molecular level, T cell proliferation and functions are therefore regulated by a complex network of transcriptional and post-transcriptional mechanisms that integrate extracellular cues to finally provide responses appropriately tailored against each invading pathogen or noxious agent. Such regulatory mechanisms include transcription factors, epigenetic modifications, signaling molecules and also microRNAs (miRNAs).

MiRNAs are short (∼21–23 nucleotides) non-coding RNAs that act post-transcriptionally by targeting primarily the 3′ untranslated regions (3′ UTRs) of cellular mRNA transcripts, in order to negatively regulate their expression [2]. The mature miRNAs derive from longer primary transcripts that undergo multiple steps of processing, mediated by the RNase III enzymes Drosha and Dicer [3]. Due to their short length and to the fact that they recognize their target mRNAs through imperfect base pairing [4], each miRNA can potentially affect multiple mRNAs, and consequently influence several downstream cellular pathways. The general importance of miRNAs in T cell biology is revealed by the many instances in which they were shown to have key roles in regulating lymphocyte development, differentiation and functions. For example, genetic ablation of the core enzymes crucial for miRNA biogenesis and maturation, namely Drosha and Dicer, caused reduced number and survival of T cells in vivo due to global impairment of miRNA expression, underlining the essential role of miRNAs in T cell development [[5], [6], [7]]. Specifically, deletion of Dicer early in T cell development impaired the survival of T cells expressing the αβ subunits of the T cell receptor (TCR), while γδ-expressing cells were not compromised [7]. Deletion of Dicer at later stages of differentiation led to a severe reduction in the development of CD8⁺ cytotoxic T cells, and to a reduced number and altered polarization of CD4⁺ T_H lymphocytes [5]. Global impairment of miRNA processing in differentiated, mature T_H cells affected cell proliferation and effector functions, as shown by the fact that cells lacking Dicer, Drosha or DGCR8 (a binding partner of Drosha) exhibited similar defects, namely increased expression of the cytokine interferon (IFN)-γ and reduced proliferation rate, pointing towards a key role for miRNAs in modulating T cell polarization and responses [6,8]. While T cell biology is clearly affected by the overall impairment of miRNA expression, individual miRNAs are also able to influence functionality and pathogenicity of T lymphocytes, as discussed below.

As for a role of miRNAs in disease, evidences from miRNA profiling experiments suggest that pathological conditions like lymphomas, hematological cancers and autoimmune diseases are also influenced by mutations or dysregulated expression of miRNAs [9]. Indeed, about half of the human miRNA genes can be found at fragile sites of the chromosomes, which are regions susceptible to modifications involved in malignant cell transformation [10]. Moreover, a systematic analysis of miRNA expression in more than 300 human samples was able to classify multiple tumor types based on miRNA expression levels, which were found to be generally downregulated compared to normal tissues. This analysis also provided more accurate information about developmental lineage and differentiation state of the tumor types with respect to classic mRNA profiling [11].

Here, we will discuss how miRNA expression in T lymphocytes can directly and indirectly affect oncogenic transformation, and we will focus primarily on three extensively studied miRNAs known to influence many aspects of T cell biology, namely miR-155, miR-146a and miR-181a. These miRNAs modulate proliferation, activation, inflammation and immune surveillance, with opposing roles in enhancing (oncomiRs) or restricting (oncosuppressor miRNAs) oncogenic transformation, representing therefore a general example of how miRNAs can affect T cell function in cancer. Indeed, dysregulated expression of these miRNAs was linked to different neoplastic diseases, and their ablation or overexpression was shown to be functionally relevant for cancer development [[12], [13], [14]]. In light of the current data, we will comment on how these miRNAs can affect both malignant transformation of T lymphocytes and immune surveillance (Fig. 1). While we will mainly focus on miR-155, miR-146a and miR-181a as examples, many other miRNAs (e.g. the miR-17~92 cluster and the miR-29 family) have been thoroughly studied in the context of lymphocyte responses or cancer development, and we refer the reader to more comprehensive recent reviews on the topic [[15], [16], [17]].