miR-aculous new avenues for cancer immunotherapy

Abstract

The rising toll of cancer globally necessitates ingenuity in early detection and therapy. In the last decade, the utilization of immune signatures and immune-based therapies has made significant progress in the clinic; however, clinical standards leave many current and future patients without options. Non-coding RNAs, specifically microRNAs, have been explored in pre-clinical contexts with tremendous success. MicroRNAs play indispensable roles in programming the interactions between immune and cancer cells, many of which are current or potential immunotherapy targets. MicroRNAs mechanistically control a network of target genes that can alter immune and cancer cell biology. These insights provide us with opportunities and tools that may complement and improve immunotherapies. In this review, we discuss immune and cancer cell-derived miRNAs that regulate cancer immunity and examine miRNAs as an integral part of cancer diagnosis, classification, and therapy.

Keywords: TME (tumor microenvironment); cancer cell; cancer immunity and immunotherapy; cell death; exosomes; metabolism; microRNA.

Figure 1

T-cell miRNAs regulate the function of CTLs and helper T-cell subsets in the TME. T-cell miRNAs regulate proinflammatory anti-tumorigenic and anti-inflammatory protumorigenic T cells in the TME. Several miRNAs regulate the fate and function of multiple T-cell subtypes, all of which play defined roles in cancer progression and elimination. These miRNAs and respective targets give mechanistic insights into potential therapeutic targets and agents.

Figure 2

miRNAs regulate T-cell inhibitory checkpoint molecules many of which are targets of clinical immune checkpoint blockade. Each miRNA can target multiple checkpoint molecules, providing a novel tool to target multiple nonoverlapping pathways.

Figure 3

Natural killer cell miRNAs regulate tumor cell recognition and NK cell function. NK cells have many surface stimulatory and inhibitory molecules required for recognizing and targeting cancer cells. Not only do miRNAs regulate these molecules, but they also regulate the adaptor proteins, DAP12, and effector molecules, including IFN-γ, Gzmb, and Pfn.

Figure 4

Dendritic cell miRNAs regulate pro- and anti-tumor immune responses in the TME. Dendritic cells are a central hub for priming pro- and anti-tumor immune responses in cancer. Many DC miRNAs change TAA presentation to and co-stimulation of T cells, required for T-cell–mediated anti-tumor immunity. Several other miRNAs suppress the proinflammatory functions and promote the immune suppressive function of DCs.

Figure 5

Macrophage miRNAs regulate pro- and anti-inflammatory macrophage skewing and function. Macrophages exist on a continuum on the M1–M2 axis. M1 macrophages are considered proinflammatory and promote anti-tumor functions, whereas M2 macrophages are anti-inflammatory and immune suppressive. Macrophage miRNAs post-transcriptionally reinforce the identity of and regulate the effector function of M1/M2 macrophages.

Figure 6

Myeloid-derived suppressor cell miRNAs alter the immune-suppressive capacity of MDSCs. MDSCs have many mechanisms to inhibit anti-tumor T-cell responses and promote tumor progression. Most MDSC miRNAs promote Arginase and iNOS-mediated CD4+ and CD8+ T-cell suppression. Conversely, several miRNAs promote the maturation of MDSCs into proinflammatory myeloid cells with anti-tumor and M1 macrophage functions. miR-155 can inhibit MDSC suppressive function, tumor vascularization, and metastatic potential; although its role in MDSC function is controversial.

Figure 7

Tumor cell miRNAs regulate immune and cancer cell functions, influencing various aspects of anti-tumor immunity. Tumor-cell expressed miRNAs regulate various aspects of the anti-tumor immunity. Studies have shown that miRNAs can impact tumor antigenicity by controlling DNA repair and antigen presentation machinery. Furthermore, miRNAs can inhibit mediators of cell death, including caspases and death receptors, to prevent immunologic cell death. miRNA-mediated control of immunomodulatory cytokines and metabolic mediators such as lactate dehydrogenase (LDH) and indoleamine 2 3-dioxygenase (IDO) can alter the immune landscape within the tumor microenvironment. Importantly, tumor-derived miRNAs can be transported via extracellular vesicles into a variety of immune cells, including dendritic cells (DCs), macrophages (Macs), myeloid-derived suppressor cells (MDSCs), and T cells, and regulate their functions. Several miRNAs regulate multiple pathways simultaneously, suggesting that the critical miRNA regulatory hubs can be targeted to potentiate anti-tumor immunity.