Abstract
MicroRNAs (miRNA), small noncoding RNAs that regulate gene expression, exist not only in cells but also in a variety of body fluids. These circulating miRNAs could enable intercellular communication. miRNAs are packaged in membrane-encapsulated vesicles, such as exosomes, or protected by RNA-binding proteins. Here, we report that miRNAs included in human melanoma exosomes regulate the tumor immune response. Using microscopy and flow cytometry, we demonstrate that CD8+ T cells internalize exosomes from different tumor types even if these cells do not internalize vesicles as readily as other immune cells. We explored the function of melanoma-derived exosomes in CD8+ T cells and showed that these exosomes downregulate T-cell responses through decreased T-cell receptor (TCR) signaling and diminished cytokine and granzyme B secretions. The result reduces the cells' cytotoxic activity. Using mimics, we found that miRNAs enriched in exosomes-such as Homo sapiens (hsa)-miR-3187-3p, hsa-miR-498, hsa-miR-122, hsa-miR149, and hsa-miR-181a/b-regulate TCR signaling and TNFα secretion. Our observations suggest that miRNAs in melanoma-derived exosomes aid tumor immune evasion and could be a therapeutic target.
Highlights
In the last decade, noncoding RNAs have emerged as a class of regulators of cellular functions and differentiation
Extracellular miRNAs secreted by tumor cells may be delivered into recipient cells in the microenvironment where they will function as endogenous miRNAs leading to altered gene expression
Our study describes this mechanism in human melanoma
Summary
In the last decade, noncoding RNAs have emerged as a class of regulators of cellular functions and differentiation. MicroRNAs (miRNA) are endogenous noncoding RNAs about 19 to 22 nucleotides (NT) that modulate gene expression through mRNA silencing or degradation [1]. A single miRNA has the capacity to inhibit several different mRNA targets. More than 60% of human genes are regulated by miRNAs [2]. MiRNAs may act in cancer as tumor suppressors (TS-miR) or oncogenes (oncomiR), depending on tissue, cellular context, and target genes [3, 4]. MiRNAs are detectable both in tumor tissues and in body fluids in extracellular vesicles, such as exosomes [5] where they participate in intercellular communication. The loading of miRNAs into exosomes is a selective process [6].
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