title: Global transcriptome-wide analysis of CIK cells identify distinct roles of IL-2 and IL-15 in acquisition of cytotoxic capacity against tumor.
abstract: BACKGROUND
  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.
authors.forename: Wenju
authors.initials: W
authors.lastname: Wang
authors.forename: Mingyao
authors.initials: M
authors.lastname: Meng
authors.forename: Yayong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chuanyu
authors.initials: C
authors.lastname: Wei
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Xie
authors.forename: Lihong
authors.initials: L
authors.lastname: Jiang
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tang
authors.forename: Xingfang
authors.initials: X
authors.lastname: Jin
authors.forename: Dai
authors.initials: D
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Zong
authors.affiliation: Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, People's Republic of China. hzl579@163.com.
authors.forename: Zongliu
authors.initials: Z
authors.lastname: Hou
authors.forename: Ruhong
authors.initials: R
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055612:Cytokine-Induced Killer Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D017423:Sequence Analysis, RNA
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2
references.citation: Genome Res. 2007 Oct;17(10):1537-45
references.pmid: 17785539
references.citation: Haematologica. 2004 Mar;89(3):338-47
references.pmid: 15020274
references.citation: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D428-32
references.pmid: 15608231
references.citation: Tumour Biol. 2014 Mar;35(3):1997-2007
references.pmid: 24104501
references.citation: Development. 2012 Dec 1;139(23):4461-72
references.pmid: 23095882
references.citation: Oncogene. 2003 Mar 13;22(10):1501-10
references.pmid: 12629513
references.citation: Blood. 2001 Jan 1;97(1):14-32
references.pmid: 11133738
references.citation: Bioinformatics. 2009 Jun 1;25(11):1470-1
references.pmid: 19307239
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1083-8
references.pmid: 17317815
references.citation: Bioinformatics. 2008 May 1;24(9):1175-82
references.pmid: 18310618
references.citation: Cytotherapy. 2012 Jan;14(1):91-103
references.pmid: 21973023
references.citation: PLoS One. 2012;7(9):e44802
references.pmid: 23028626
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D277-80
references.pmid: 14681412
references.citation: J Immunol. 2012 Jun 1;188(11):5521-7
references.pmid: 22547704
references.citation: J Immunol. 1999 May 15;162(10):5813-20
references.pmid: 10229815
references.citation: J Biomed Biotechnol. 2010;2010:435745
references.pmid: 20368995
references.citation: Bioinformatics. 2012 Aug 15;28(16):2184-5
references.pmid: 22743226
references.citation: PLoS One. 2012;7(11):e50411
references.pmid: 23226279
references.citation: Nat Med. 2012 Aug;18(8):1224-31
references.pmid: 22820642
references.citation: J Transl Med. 2013 Mar 28;11:83
references.pmid: 23536996
references.citation: Genome Res. 2002 Jan;12(1):37-46
references.pmid: 11779829
references.citation: J Exp Med. 1994 Oct 1;180(4):1395-403
references.pmid: 7523571
references.citation: BMC Bioinformatics. 2006 Jan 19;7:30
references.pmid: 16423281
references.citation: Bioinformatics. 2005 Jul 1;21(13):3017-24
references.pmid: 15840707
references.citation: J Exp Med. 2002 Oct 7;196(7):935-46
references.pmid: 12370255
references.citation: Nat Rev Genet. 2004 Feb;5(2):101-13
references.pmid: 14735121
references.citation: Immunity. 2001 Feb;14(2):105-10
references.pmid: 11239443
references.citation: Nat Immunol. 2012 Mar 04;13(4):387-95
references.pmid: 22388039
references.citation: Clin Cancer Res. 2013 Oct 15;19(20 Suppl):S4-98
references.pmid: 24045178
references.citation: Biochim Biophys Acta. 2010 Aug;1806(1):122-30
references.pmid: 20434526
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Circ Res. 2011 Feb 18;108(4):427-36
references.pmid: 21193738
references.citation: Curr Drug Targets. 2009 Jan;10(1):38-41
references.pmid: 19149534
references.citation: Bioinformatics. 2007 Jun 15;23(12):1537-44
references.pmid: 17483504
references.citation: Science. 2002 Aug 30;297(5586):1551-5
references.pmid: 12202830
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: J Clin Oncol. 2001 Jul 1;19(13):3280-7
references.pmid: 11432896
references.citation: Genome Biol. 2010;11(10):R106
references.pmid: 20979621
references.citation: Cancer Res. 2007 Dec 1;67(23):11377-85
references.pmid: 18056465
references.citation: PLoS One. 2013;8(4):e60045
references.pmid: 23577081
references.citation: Mol Cell Biol. 2000 Aug;20(15):5503-15
references.pmid: 10891490
references.citation: PLoS One. 2013 Jul 03;8(7):e67434
references.pmid: 23844010
references.citation: J Exp Med. 1991 Jul 1;174(1):139-49
references.pmid: 1711560
references.citation: Breast Cancer Res Treat. 2011 Feb;126(1):15-25
references.pmid: 20379844
references.citation: Cancer Res. 2012 Feb 1;72(3):592-603
references.pmid: 22139376
references.citation: PLoS One. 2008;3(12):e3911
references.pmid: 19081792
references.citation: Nucleic Acids Res. 2010 Oct;38(18):e178
references.pmid: 20802226
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D322-6
references.pmid: 16381878
references.citation: Nature. 2005 Apr 14;434(7035):843-50
references.pmid: 15829953
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: PLoS One. 2013 Jul 23;8(7):e69044
references.pmid: 23935919