Abstract
Studies have proven that IL-2 and IL-15 showed contrasting roles during CIK cells preparation. By employing microarray, we analyzed miRNA expression profiles of PBMC, CIKIL-2 and CIKIL-15. Advanced bioinformatic analyses were performed to explore the key miRNAs which may regulate cell proliferation and anti-tumor activity of CIK. We identified 261 differentially expressed miRNAs (DEMs) between PBMC and CIKIL-2, and 249 DEMs between PBMC and CIKIL-15. MiR-143-3p/miR-145-5p was miRNA cluster which may positively regulate cell proliferation. In contrast, miR-340-5p/miR-340-3p cluster may negatively regulate cell proliferation via induction apoptosis, which may cause decreased cell proliferation capacity of CIKIL-2. MiRNA-target interaction analysis indicated that 10 co-downregulated miRNAs may synergistically turn on the expression of a pool of tumor cytotoxic genes in CIK cells. The DEMs between CIKIL-2 and CIKIL-15 may contribute to enhanced tumor cytotoxic capacity of CIKIL-2. Importantly, we found that repressed miR-193a-5p may regulate the expressions of inhibitory receptor KLRD1. The results of the validation assay have shown that KLRD1 were upregulated in CIK cells. Our findings have provided new insights into mechanisms of CIK cells production and tumor cytotoxic function, and shed light on their safety for clinical trial.
Highlights
Studies have proven that IL-2 and IL-15 showed contrasting roles during Cytokine-induced killer (CIK) cells preparation
By advanced bioinformatic analysis of RNA-seq data from CIKIL-2 and CIKIL-15, results indicated that genes participating in Wnt signal pathway and focal adhesion were upregulated in CIKIL-15, and the expression levels of genes involved in cytokine-cytokine receptor interaction were increased in CIKIL-210
After confirmation of the portion of CD31CD561 cells, the proliferation capacity and tumor cytotoxicity of both CIKIL-2 and CIKIL-15 were measured by automatic absolute cell counting and CCK-8 based method respectively
Summary
Studies have proven that IL-2 and IL-15 showed contrasting roles during CIK cells preparation. The protocol for preparation of CIK cells can be differed for the purpose of enhancing the tumor cytotoxicity and CIK cells proliferation capacity[7]. We have shown that CIK cells stimulated with combination of IL-2 and IL-15 exhibited enhanced proliferation capacity and cytotoxicity against lung cancer[9]. The regulatory functions of miRNAs in CIK cells expansion and acquisition of cytotoxic capacity have not been reported yet. In order to identify the roles of miRNAs in regulatory network of CIK cells generation, we performed miRNAs microarray analysis between PBMC (peripheral blood mononuclear cell) and CD31CD561 CIK cells, and investigated the changes in global miRNAs expression level. Our finding will provide evidence to better understand the acquisition of tumor cytotoxicity and proliferation capacity of CIK cells
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