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

AbstractBACKGROUND:
Cytokine-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.
METHODS:
CIK(IL-2) and CIK(IL-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.
RESULTS:
The results indicated that CIKIL-15 showed improved cell proliferation capacity compared to CIK(IL-2). However, CIK(IL-2) has exhibited greater tumor cytotoxic effect than CIKIL-15. Employing deep sequencing, we sequenced mRNA transcripts in CIK(IL-2) and CIK(IL-15). A total of 374 differentially expressed genes (DEGs) were identified including 175 up-regulated genes in CIK(IL-15) and 199 up-regulated genes in CIK(IL-2)). Among DEGs in CIK(IL-15), Wnt signaling and cell adhesion were significant GO terms and pathways which related with their functions. In CIK(IL-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 CIK(IL-15), while inhibitory signal from interaction between CTLA4 and CD80 may be responsible for the weak proliferation capacity of CIK(IL-2). Moreover, up-regulated expressions of CD40LG and IRF7 may make for improved tumor cytolytic function of CIK(IL-2) through type I interferon signaling.
CONCLUSIONS:
Through our findings, we have preliminarily elucidated the cells proliferation and acquisition of tumor cytotoxicity mechanism of CIK(IL-15) and CIK(IL-2). Better understanding of these mechanisms will help to generate novel CIK cells with greater proliferation potential and improved tumor cytolytic function.
AuthorsWenju Wang, Mingyao Meng, Yayong Zhang, Chuanyu Wei, Yanhua Xie, Lihong Jiang, Chunhui Wang, Fang Yang, Weiwei Tang, Xingfang Jin, Dai Chen, Jie Zong, Zongliu Hou, Ruhong Li
JournalBMC medical genomics (BMC Med Genomics) Vol. 7 Pg. 49 (Aug 09 2014) ISSN: 1755-8794 [Electronic] England
PMID25108500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Interleukin-15
  • Interleukin-2
Topics
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cytokine-Induced Killer Cells (cytology, drug effects, metabolism)
  • Gene Expression Profiling
  • Gene Ontology
  • Gene Regulatory Networks (drug effects)
  • Humans
  • Interleukin-15 (pharmacology)
  • Interleukin-2 (pharmacology)
  • Neoplasms (genetics, immunology)
  • Sequence Analysis, RNA

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