Abstract
Exosomes have been introduced as a new alternative delivery system for the transmission of small molecules. Tumor-derived exosomes (TEXs) not only contain tumor-associated antigens to stimulate antitumor immune responses but also act as natural carriers of microRNAs. The aim of the current study was to evaluate the efficacy of miR-124-3p-enriched TEX (TEXomiR) as cell-free vaccine in the induction of antitumor immune responses in a mouse model of colorectal cancer. Briefly, the exosomes were isolated from cultured CT-26 cell line, and modified calcium chloride method was used to deliver miR-124-3p mimic into the exosomes. We used a CT-26-induced BALB/c mouse model of colorectal cancer and analyzed the effect of TEXomiR on survival, tumor size, spleen and tumor-infiltrated lymphocytes, and splenocyte proliferation. Furthermore, intra-tumor regulatory T cells, cytotoxic activity of the splenocytes, and cytokine secretion was also evaluated to describe the anti-tumor immune response. When the tumor size reached 100 mm3, the mice were injected with TEXomiR, TEX, and/or phosphate-buffered saline (PBS) subcutaneously three times with 3-day interval, and then tumor size was monitored every 2 days. The in vitro results indicated that TEXs could efficiently deliver functional miR-124-3p mimic. The in vivo evaluation in tumor-bearing mice showed that treatment with TEXomiR can elicit a stronger anti-tumor immune response than unloaded TEX and PBS. Significant tumor growth inhibition and increased median survival time was achieved in tumor-bearing mice treated with TEXomiR. A significant decrease in CD4/CD8 and Treg/CD8 ratio in tumor tissue was demonstrated. Moreover, increased cytotoxicity and proliferation of splenocytes in the TEXomiR group compared to the TEX and PBS groups were identified. Taken together, our data demonstrated that tumor-derived exosomes efficiently deliver miR-124-3p mimic, and TEXomiR promotes anti-tumor immune responses.
Highlights
Colorectal cancer (CRC) is the third leading cause of deaths among all human cancers
The results indicated a significant reduction of STAT3, SP1, and SOCS5 mRNA expression in the splenocytes of CT-26 tumor-bearing mice treated with TEXomiR compared to both the Tumor-derived exosomes (TEXs) and phosphate-buffered saline (PBS) groups (P < 0.01)
The relative expression of STAT3, SOCS5, and SP1 in the TEXomiR group compared to the TEX and PBS groups were as follows: (0.2 ± 0.11 vs. 0.7 ± 0.23 and 1 ± 0.2, P = 0.0029), (0.16 ± 0.09 vs. 1.2 ± 0.4 and 1 ± 0.3, P = 0.00089), and (0.3 ± 0.15 vs. 0.77 ± 0.1 and 1 ± 0.4, P = 0.0073), respectively
Summary
Colorectal cancer (CRC) is the third leading cause of deaths among all human cancers. Its overall incidence is ∼5%, and the 5-year survival rate varies from 40 to 60% [1] Changes in the expression profile of miRNAs in CRC have been well-documented [5]. Several studies have shown that miRNAs can act as tumor suppressors or oncogenes and are commonly dysregulated in tumor [5, 6]. Several studies have evaluated microRNA expression profiles in CRC and authenticated that microRNAs are reproducibly and consistently altered in this malignancy [9, 10]. Dysregulation of the 164 microRNAs has been illustrated in CRC; ∼66% of them were increased, and the remaining were decreased in this disease [5]
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