Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma

Abstract

Tumor-derived exosomes contain biologically active proteins and messenger and microRNAs (miRNAs). These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape. Here, we isolated 30-100 nm exosomes from the serum of patients with nasopharyngeal carcinoma (NPC) or the supernatant of TW03 cells. Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients (P < 0.05). TW03-derived exosomes impaired T-cell function by inhibiting T-cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro. These results are associated with decreases in ERK, STAT1, and STAT3 phosphorylation and increases in STAT5 phosphorylation in exosome-stimulated T-cells. TW03-derived exosomes increased the proinflammatory cytokines IL-1β, IL-6, and IL-10 but decreased IFNγ, IL-2, and IL-17 release from CD4+ or CD8+ T-cells. Furthermore, five commonly over-expressed miRNAs were identified in the exosomes from patient sera or NPC cells: hsa-miR-24-3p, hsa-miR-891a, hsa-miR-106a-5p, hsa-miR-20a-5p, and hsa-miR-1908. These over-expressed miRNA clusters down-regulated the MARK1 signaling pathway to alter cell proliferation and differentiation. Overall, these observations reveal the clinical relevance and prognostic value of tumor-derived exosomes and identify a unique intercellular mechanism mediated by tumor-derived exosomes to modulate T-cell function in NPC.

Exosomes and tumor-mediated immune suppression

“…TEX have been called "oncomirs," and the miR content of TEX has been extensively investigated (85). miRs regulate gene expression in recipient cells by either repressing translation or inducing degradation of multiple target mRNAs, depending on the cellular context (84,86). The transfer of miRs from tumor to immune cells alters their functions, usually downregulating antitumor activities and promoting tumorigenesis (84).…”

Low expression of microRNA-1908 predicts a poor prognosis for patients with ovarian cancer

“…The dysregulation of miRNA expression is associated with a range of diseases, including the development of tumors (3). miR-1908 is regarded as an oncogene in numerous types of tumor (4). The miRNA functions as an oncogene through suppressing phosphatase and tensin homolog (PTEN), a tumor suppressor; this function promotes the proliferation and invasiveness of tumor cells in glioblastoma and osteosarcoma (5).…”

Exosomes as the Promising Biomarker for Epstein-Barr Virus (EBV)-Associated Cancers

“…Choi and colleagues demonstrated that the miR-BART15-3p could be detected in EBV-associated exosomes and its expression level was 2 to 16-fold higher in the exosomes compared with the cellular level in GC cells [44], hence suggesting its potential tumorigenic role. On the other hand, Ye and group showed that the exosomal miRNAs promoted the tumour progression by modulating multiple cellular processes in NPC [45] ( Table 1). Further studies are required to investigate and validate their roles in promoting EBV-derived cancers.…”