title: Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides.
abstract: We explored the mechanisms of class B CpG-oligodeoxynucleotide-induced antitumour effects against weakly immunogenic tumours. Treatment with CpG-oligodeoxynucleotide 1826 (CpG) induced similar antitumour effects in B16 melanoma-bearing immunocompetent C57BL/6 mice and T-cell-deficient severe combined immunodeficient (SCID) mice, and NXS2 neuroblastoma-bearing T-cell-depleted A/J mice. Both macrophages (Mphi) and natural killer (NK) cells from CpG-treated C57BL/6 mice could mediate cytotoxicity in vitro, suggesting that these cell types might control tumour growth in vivo. However, CpG treatment of SCID/beige mice or T-cell-depleted and NK-cell-depleted A/J mice still induced antitumour effects in vivo, arguing against a major role of NK cells in the antitumour effects of CpG in the absence of T cells. In contrast, CpG treatment of interferon-gamma knockout (IFN-gamma(-/-)) C57BL/6 mice resulted in no antitumour effects in vivo and no Mphi-mediated tumoristasis in vitro despite unaltered cytolytic function of NK cells in vitro. Moreover, Mphi inactivation by silica substantially reduced CpG-induced suppression of tumour growth in vivo, revealing an important role of Mphi in CpG-induced antitumour effects. The in vitro tumouritoxicity by CpG-stimulated Mphi (CpG-Mphi) correlated with tumour cell mitochondria dysfunction and involved nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma, whereas interleukin-1alpha (IL-1alpha), IL-1beta, IFN-alpha, TNF-related apoptosis-inducing ligand and Fas ligand played insignificant roles in CpG-Mphi tumouritoxicity. Taken together, our results indicate that the growth control of weakly immunogenic tumours during CpG-immunotherapy is mediated predominantly by Mphi, rather than T cells or NK cells.
authors.affiliation: Department of Human Oncology, The University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-4672, USA. buhtoiarov@humonc.wisc.edu
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Buhtoiarov
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma