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

Abstract

// Shu-biao Ye 1,2,3 , Ze-Lei Li 1,2,3 , Dong-hua Luo 1,2,4 , Bi-jun Huang 1,2 , Yu-Suan Chen 1,2,5 , Xiao-shi Zhang 1,2,3 , Jun Cui 6 , Yi-xin Zeng 1,2 and Jiang Li 1,2,3 1 State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China 2 Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China 3 Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, China 4 Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China 5 Department of Radiotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, China 6 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-sen University, Guangzhou, China Correspondence: Jiang Li, email: // Keywords : exosomes, nasopharyngeal carcinoma, tumor microenvironment Received : May 7, 2014 Accepted : June 17, 2014 Published : June 19, 2014 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.