title: Role of type 1 IFNs in antiglioma immunosurveillance--using mouse studies to guide examination of novel prognostic markers in humans.
abstract: OBJECTIVE
  We hypothesized that the type 1 IFNs would play a pivotal role in antiglioma immunosurveillance through promotion of type 1 adaptive immunity and suppression of immunoregulatory cells.
  
  
  METHODS
  We induced de novo gliomas in Ifnar1(-/-) (deficient for type 1 IFN receptors) or wild-type mice by intracerebroventricuar transfection of NRas and a short hairpin RNA against P53 using the Sleeping Beauty transposon system. We analyzed the survival of 587 glioma patients for single nucleotide polymorphisms (SNP) in type 1 IFN-related genes.
  
  
  RESULTS
  Ifnar1(-/-) mice exhibited accelerated tumor growth and death. Analyses of brain tumor-infiltrating lymphocytes in Ifnar1(-/-) mice revealed an increase of cells positive for CD11b(+)Ly6G(+) and CD4(+)FoxP3(+), which represent myeloid-derived suppressor cells and regulatory T cells, respectively, but a decrease of CD8(+) cytotoxic T lymphocytes (CTLs) compared with wild-type mice. Ifnar1(-/-) mouse-derived glioma tissues exhibited a decrease in mRNA for the CTL-attracting chemokine Cxcl10, but an increase of Ccl2 and Ccl22, both of which are known to attract immunoregulatory cell populations. Dendritic cells generated from the bone marrow of Ifnar1(-/-) mice failed to function as effective antigen-presenting cells. Moreover, depletion of Ly6G(+) cells prolonged the survival of mice with developing gliomas. Human epidemiologic studies revealed that SNPs in IFNAR1 and IFNA8 are associated with significantly altered overall survival of patients with WHO grade 2 to 3 gliomas.
  
  
  CONCLUSIONS
  The novel Sleeping Beauty-induced murine glioma model led us to discover a pivotal role for the type 1 IFN pathway in antiglioma immunosurveillance and relevant human SNPs that may represent novel prognostic markers.
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Decker
authors.forename: Heather A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kato
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bondy
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001932:Brain Neoplasms / Q000191:economics* / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D054357:Chemokine CXCL10; D003713:Dendritic Cells / Q000276:immunology; D005910:Glioma / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015166:Monitoring, Immunologic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta
references.citation: Cancer Res. 2008 Jul 15;68(14):5972-8
references.pmid: 18632653
references.citation: J Neurosurg. 2009 Mar;110(3):572-82
references.pmid: 19199469
references.citation: J Leukoc Biol. 2008 Jan;83(1):64-70
references.pmid: 17884993
references.citation: Nat Rev Immunol. 2006 Nov;6(11):836-48
references.pmid: 17063185
references.citation: J Neurooncol. 2009 Jan;91(2):183-9
references.pmid: 18850068
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):2148-57
references.pmid: 19276286
references.citation: Clin Cancer Res. 2004 Apr 15;10(8):2618-25
references.pmid: 15102663
references.citation: Cancer. 2001 Jul 15;92(2):420-33
references.pmid: 11466698
references.citation: Nat Med. 2007 Sep;13(9):1050-9
references.pmid: 17704786
references.citation: J Immunol. 1993 Sep 1;151(5):2399-408
references.pmid: 8360469
references.citation: J Immunol. 2008 Feb 15;180(4):2089-98
references.pmid: 18250414
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6640-6
references.pmid: 18927306
references.citation: J Clin Oncol. 2008 Dec 20;26(36):5957-64
references.pmid: 19001328
references.citation: Cancer Res. 2009 Jan 15;69(2):431-9
references.pmid: 19147555
references.citation: J Transl Med. 2007 Feb 12;5:10
references.pmid: 17295916
references.citation: Annu Rev Immunol. 2008;26:453-79
references.pmid: 18062768
references.citation: J Neurooncol. 2009 Jan;91(2):175-82
references.pmid: 18797818
references.citation: J Biol Chem. 2007 Jul 13;282(28):20053-7
references.pmid: 17502368
references.citation: N Engl J Med. 2008 Oct 2;359(14):1456-63
references.pmid: 18753640
references.citation: Nat Rev Neurol. 2009 Aug;5(8):419-26
references.pmid: 19597514
references.citation: Science. 1992 Jul 24;257(5069):548-51
references.pmid: 1636093
references.citation: Nat Immunol. 2005 Jul;6(7):722-9
references.pmid: 15951814
references.citation: Cancer Lett. 2007 Jul 8;252(1):86-92
references.pmid: 17257744
references.citation: Cancer Res. 2006 Apr 15;66(8):4531-41
references.pmid: 16618782
references.citation: Crit Rev Immunol. 2009;29(1):1-42
references.pmid: 19348609
references.citation: Clin Cancer Res. 2005 Sep 15;11(18):6713-21
references.pmid: 16166452
references.citation: Cancer Res. 2006 Apr 15;66(8):4478-87
references.pmid: 16618775
references.citation: Neurosurgery. 1996 Jun;38(6):1096-103; discussion 1103-4
references.pmid: 8727138
references.citation: Ann N Y Acad Sci. 2009 Sep;1174:99-106
references.pmid: 19769742
references.citation: Cancer Res. 2009 Feb 15;69(4):1587-95
references.pmid: 19190335
references.citation: Cancer Res. 2005 Jul 15;65(14):6459-65
references.pmid: 16024651
references.citation: Nat Rev Cancer. 2004 Nov;4(11):850-60
references.pmid: 15516958
references.citation: Clin Cancer Res. 2009 Nov 1;15(21):6560-9
references.pmid: 19861451
references.citation: Nat Rev Immunol. 2006 Apr;6(4):295-307
references.pmid: 16557261
references.citation: J Exp Med. 1998 Jul 20;188(2):277-86
references.pmid: 9670040
references.citation: J Immunol. 1995 Aug 1;155(3):1151-64
references.pmid: 7636184
references.citation: Annu Rev Immunol. 2004;22:329-60
references.pmid: 15032581
references.citation: Cancer Immunol Immunother. 2008 Jan;57(1):123-31
references.pmid: 17522861
references.citation: Mol Ther. 2005 Nov;12(5):778-88
references.pmid: 16150649
references.citation: Vaccine. 2008 Mar 25;26(14):1731-6
references.pmid: 18325643