title: Lymphoma B-cell responsiveness to CpG-DNA depends on the tumor microenvironment.
abstract: BACKGROUND
  Toll-like receptor (TLR) agonists have important properties that can be exploited for immunotherapy against tumors. Locally injected immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG-ODNs), which are TLR9 agonists, have shown promise in cancer models. Several studies have demonstrated that these motifs have immunologic effects similar to those of bacterial DNA and can stimulate monocytes, macrophages, dendritic, and B cells, which then produce several proinflammatory cytokines. However, these CpG-ODNs appear to produce opposite effects on tumor B cells.
  
  
  METHODS
  In this study, we investigated the direct effects of a murine class B CpG (1826) ODNs on lymphoma B cells in vitro and in vivo, using mouse models of non-Hodgkin B lymphomas developing in immunoprivileged sites, specifically the brain and the eye, and in subcutaneous sites.
  
  
  RESULTS
  In vitro, CpG-ODNs produced antiproliferative and proapoptotic effects on lymphoma B cells. In vivo, it had an antitumor effect when injected into tumors in murine models of subcutaneous lymphoma (SCL) and primary cerebral lymphoma (PCL). However, its intravitreal administration into a primary intraocular lymphoma (PIOL) mouse model did not produce an antitumor effect. In vitro experiments using supernatant from mouse PIOL samples demonstrated that the PIOL molecular microenvironment inhibits the antiproliferative effect of CpG-ODNs on lymphoma B-cells.
  
  
  CONCLUSIONS
  Responsiveness to CpG stimulation differs in subcutaneous, cerebral, and ocular tumors, according to the tumoral and molecular microenvironment, and this should be considered for further therapeutic approaches.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS872, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Rym
authors.initials: R
authors.lastname: Ben Abdelwahed
authors.forename: Jérémie
authors.initials: J
authors.lastname: Cosette
authors.forename: Sabrina
authors.initials: S
authors.lastname: Donnou
authors.forename: Lucile
authors.initials: L
authors.lastname: Crozet
authors.forename: Hanane
authors.initials: H
authors.lastname: Ouakrim
authors.forename: Wolf Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
authors.forename: Aouni
authors.initials: A
authors.lastname: Mahjoub
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fisson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D018899:CpG Islands; D004273:DNA, Neoplasm / Q000235:genetics*; D004195:Disease Models, Animal; D005134:Eye Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D051217:Toll-Like Receptor 9 / Q000819:agonists; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics*
chemical_list: C408982:CPG-oligonucleotide; D004273:DNA, Neoplasm; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9
references.citation: Adv Drug Deliv Rev. 2009 Mar 28;61(3):263-7
references.pmid: 19168102
references.citation: J Immunol. 2000 Jan 15;164(2):944-53
references.pmid: 10623843
references.citation: J Immunol. 2007 Aug 15;179(4):2493-500
references.pmid: 17675511
references.citation: J Leukoc Biol. 2000 Oct;68(4):455-63
references.pmid: 11037965
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10833-7
references.pmid: 9380720
references.citation: Oncogene. 2008 Jan 7;27(2):161-7
references.pmid: 18176597
references.citation: Adv Hematol. 2012;2012:701704
references.pmid: 22400032
references.citation: Trends Immunol. 2007 Jan;28(1):12-8
references.pmid: 17129764
references.citation: Inflamm Res. 2010 Oct;59(10):791-808
references.pmid: 20593217
references.citation: Curr Opin Pharmacol. 2011 Aug;11(4):404-11
references.pmid: 21501972
references.citation: Blood. 2009 Apr 9;113(15):3546-52
references.pmid: 18941113
references.citation: J Leukoc Biol. 2002 Jul;72(1):83-92
references.pmid: 12101266
references.citation: Clin Cancer Res. 2005 Feb 15;11(4):1490-9
references.pmid: 15746051
references.citation: J Immunol. 2001 Feb 15;166(4):2372-7
references.pmid: 11160295
references.citation: J Immunol. 2007 May 15;178(10):6100-8
references.pmid: 17475835
references.citation: Update Cancer Ther. 2008 Mar;3(1):27-32
references.pmid: 19255607
references.citation: Blood. 2010 Jun 17;115(24):5041-52
references.pmid: 20339095
references.citation: Leuk Lymphoma. 2008;49 Suppl 1:43-51
references.pmid: 18821432
references.citation: Nature. 1995 Apr 6;374(6522):546-9
references.pmid: 7700380