title: CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice.
abstract: The Toll-like receptor (TLR) 9 ligand CpG has been used successfully for the immunotherapy of cancer. Chronic CpG application in tumor-free hosts leads, however, to the expansion of myeloid-derived suppressor cells (MDSC), which can cause T-cell suppression and may thus hamper the development of an effective immune response. Here, we investigated the effect of TLR9 activation on the function of MDSC in tumor-bearing mice.
  
  
  
  We investigated the effect of CpG treatment on the number, phenotype, and function of MDSC in mice bearing subcutaneous C26 tumors and in CEA424-TAg mice bearing autochthonous gastric tumors.
  
  
  
  CpG treatment blocks the suppressive activity of MDSC on T-cell proliferation in both tumor models. Inhibition of MDSC function by CpG was particularly pronounced for a highly suppressive Ly6G(hi) polymorphonuclear subset of MDSC. We further show that TLR9 activation by CpG promotes maturation and differentiation of MDSC and strongly decreases the proportion of Ly6G(hi) MDSC in both tumor-bearing and tumor-free mice. We demonstrate that IFN-α produced by plasmacytoid dendritic cells upon CpG stimulation is a key effector for the induction of MDSC maturation in vitro and show that treatment of mice with recombinant IFN-α is sufficient to block MDSC suppressivity.
  
  
  
  We show here for the first time that TLR9 activation inhibits the regulatory function of MDSC in tumor-bearing mice and define a role for the antitumoral cytokine IFN-α in this process.
authors.affiliation: Division of Clinical Pharmacology and Center of Integrated Protein Science Munich, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Zoglmeier
authors.forename: Helen
authors.initials: H
authors.lastname: Bauer
authors.forename: Daniel
authors.initials: D
authors.lastname: Noerenberg
authors.forename: Georg
authors.initials: G
authors.lastname: Wedekind
authors.forename: Philipp
authors.initials: P
authors.lastname: Bittner
authors.forename: Nadja
authors.initials: N
authors.lastname: Sandholzer
authors.forename: Moritz
authors.initials: M
authors.lastname: Rapp
authors.forename: David
authors.initials: D
authors.lastname: Anz
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Carole
authors.initials: C
authors.lastname: Bourquin
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018899:CpG Islands; D004247:DNA / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016898:Interferon-alpha / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D009838:Oligodeoxyribonucleotides; D013154:Spleen / Q000166:cytology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000943:Antigens, Differentiation; D000950:Antigens, Ly; D000970:Antineoplastic Agents; D039481:CD11b Antigen; C423449:CpG ODN 1826; D007155:Immunologic Factors; D016898:Interferon-alpha; D007376:Interleukin-2; C494192:Ly-6C antigen, mouse; C480309:Ly6G antigen, mouse; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D004247:DNA