Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

Abstract

Cancer immunotherapy represents a promising new era in cancer management due to the relatively high safety margins and selectivity, compared to the classical cancer chemotherapeutic agents. However, there is an imperative need to overcome tumor resistance in order to improve clinical outcomes and maximize the benefits of cancer immunotherapy. The interaction between the programmed cell death‐1 (PD‐1) receptor and its ligand PD‐L1 is a vital immune checkpoint that is often adopted by cancer cells to undergo immune evasion. PD‐1/PD‐L1 signaling is regulated at multiple levels through the crosstalk with other immune targets or relevant signaling partners involved in the cancer progression. Among the significant epigenetic players that are implicated in modulating the immune system are microRNAs (miRNAs). A complex system of these noncoding RNAs regulates the gene expression at the post‐transcriptional level and plays a significant role in the modulation of both innate and the adaptive immune systems. The expression profile of immune‐modulatory miRNAs might be useful as a predictive biomarker for the response and clinical outcomes in cancer immunotherapy. Therefore, in the current review, we highlighted the role of miRNAs in cancer immune evasion through a critical discussion of their impact on key immune checkpoints as well as the role of miRNAs in cancer progression and resistance.

The role of cancer-derived microRNAs in cancer immune escape

“…Apart from acting as tumor promoters or suppressors, it has been revealed that a growing body of miRNAs could regulate cancer immune surveillance and escape [49]. A panel of miRNAs protect cancer cells from immune clearance by decreasing the immunogenicity of cancer cells and downregulating the magnitude of anti-cancer immune response (Fig.…”

Highly efficient serum-free manipulation of miRNA in human NK cells without loss of viability or phenotypic alterations is accomplished with TransIT-TKO

“…The high stability of miRNA, and that it is released and available in body fluids make it attractive candidates as biomarkers or for targeted therapies [16][17][18]. Although transfection techniques are numerous, efficient transfection of primary NK cells without introducing offtarget effects or skewing the NK cell population remains challenging.…”

“…The broad regulation of cellular processes by miRNA make them intriguing as agents to modulate NK cells for immunotherapy and to monitor ongoing processes. Already, miRNA species have been implicated as biomarkers for identifying and characterizing diseases or monitoring treatment efficacy [16][17][18]. Noteworthy, one miRNA-based treatment, miravirsen, is being tested against hepatitis C (clinicaltrials.gov # NCT02508090).…”

miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy

“…Recently, it has been demonstrated that some miRNAs directly target the 3 ′ -UTR of PD-L1 mRNA and others the PD-1/PD-L1 indirectly by targeting the related signaling pathways (Wang et al, 2017;Gao et al, 2019;Omar et al, 2019). miR-15a, miR-15b and miR-16 were discovered to downregulate the PD-L1 expression in malignant pleural mesothelioma cell line (Kao et al, 2017) (Figure 1D).…”