Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor

Abstract

BackgroundCytokine-induced killer (CIK) cells are an emerging approach of cancer treatment. Our previous study have shown that CIK cells stimulated with combination of IL-2 and IL-15 displayed improved proliferation capacity and tumor cytotoxicity. However, the mechanisms of CIK cell proliferation and acquisition of cytolytic function against tumor induced by IL-2 and IL-15 have not been well elucidated yet.MethodsCIKIL-2 and CIKIL-15 were generated from peripheral blood mononuclear cells primed with IFN-γ, and stimulated with IL-2 and IL-15 in combination with OKT3 respectively. RNA-seq was performed to identify differentially expressed genes, and gene ontology and pathways based analysis were used to identify the distinct roles of IL-2 and IL-15 in CIK preparation.ResultsThe results indicated that CIKIL-15 showed improved cell proliferation capacity compared to CIKIL-2. However, CIKIL-2 has exhibited greater tumor cytotoxic effect than CIKIL-15. Employing deep sequencing, we sequenced mRNA transcripts in CIKIL-2 and CIKIL-15. A total of 374 differentially expressed genes (DEGs) were identified including 175 up-regulated genes in CIKIL-15 and 199 up-regulated genes in CIKIL-2. Among DEGs in CIKIL-15, Wnt signaling and cell adhesion were significant GO terms and pathways which related with their functions. In CIKIL-2, type I interferon signaling and cytokine-cytokine receptor interaction were significant GO terms and pathways. We found that the up-regulation of Wnt 4 and PDGFD may contribute to enhanced cell proliferation capacity of CIKIL-15, while inhibitory signal from interaction between CTLA4 and CD80 may be responsible for the weak proliferation capacity of CIKIL-2. Moreover, up-regulated expressions of CD40LG and IRF7 may make for improved tumor cytolytic function of CIKIL-2 through type I interferon signaling.ConclusionsThrough our findings, we have preliminarily elucidated the cells proliferation and acquisition of tumor cytotoxicity mechanism of CIKIL-15 and CIKIL-2. Better understanding of these mechanisms will help to generate novel CIK cells with greater proliferation potential and improved tumor cytolytic function.

RETRACTED ARTICLE: Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma

“…Degree centrality is defined as the link numbers one node has to the other. 29 Co-expression network analysis showed that FABP5P3, LOC100996732, LOC100996735, ZFAS1 and ZEB1-AS1 are central lncRNAs (Supplementary Table S2). We then tested the role of these five lncRNAs in cell growth.…”

Anticancer Cytokines: Biology and Clinical Effects of Interferon-α2, Interleukin (IL)-2, IL-15, IL-21, and IL-12

“…IL-15 mainly promotes proliferation and differentiation of CD8+ T cells (56) and NK cells and serves as a homing factor in recruiting target immune cells to sites of production (57) . In comparison to IL-2, IL-15 appears to promote a more durable CD8+ memory T cell phenotype, induce more enhanced cell proliferation (58) and increase cell survival by upregulation of anti-apoptotic genes such as bcl-2 or downregulation of proapoptotic genes such as BIM and NOXA, even protecting them from IL-2 induced AICD (59, 60) .…”

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

“…Within the network analysis, degree centrality is the most simplest and important measures of the centrality of a gene within a network that determines the relative importance. Degree centrality is defined as the link numbers one node has to the other (24). Coexpression network analysis showed that FABP5P3, LOC100996735, LOC100996732, ZEB1-AS1, and ZFAS1 are core lncRNAs.…”