title: The Impact of Macrophage- and Microglia-Secreted TNFα on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment.
abstract: OBJECTIVE
  Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM.
  
  
  METHODS
  Quantitative flow cytometry of mice with intracranial gliomas (±oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNFα-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFα on virus replication. TNFα blocking antibodies were used to evaluate the impact of TNFα on oHSV therapy in vivo.
  
  
  RESULTS
  Flow-cytometry analysis revealed a 7.9-fold increase in macrophage infiltration after virus treatment. Tumor-infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFα in response to infected glioma cells in vitro and in vivo. Using TNFα-blocking antibodies and macrophages derived from TNFα-knockout mice, we discovered TNFα-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors.
  
  
  CONCLUSIONS
  The results of these studies suggest that FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy.
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: W Hans
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wohleb
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Bolyard
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Luke
authors.initials: L
authors.lastname: Russell
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jayson
authors.initials: J
authors.lastname: Hardcastle
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Samuel
authors.initials: S
authors.lastname: Dubin
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Kamaldeen
authors.initials: K
authors.lastname: Muili
authors.affiliation: Division of Hematology, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Hematology, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Michael
authors.initials: M
authors.lastname: Caligiuri
authors.affiliation: Department of Neuroscience, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Godbout
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio. Balveen.Kaur@osumc.edu.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000276:immunology* / Q000473:pathology; D018259:Herpesvirus 1, Human / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D017628:Microglia / Q000276:immunology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha
references.citation: J Infect Dis. 2002 Dec 1;186 Suppl 2:S171-9
references.pmid: 12424694
references.citation: Gene Ther. 2013 Mar;20(3):255-61
references.pmid: 22476202
references.citation: Cancer Lett. 2013 May 1;331(2):139-46
references.pmid: 23340179
references.citation: Cancer J. 2012 Jan-Feb;18(1):82-8
references.pmid: 22290261
references.citation: J Natl Cancer Inst. 2007 Dec 5;99(23):1768-81
references.pmid: 18042934
references.citation: Acta Neuropathol. 2000 Sep;100(3):323-31
references.pmid: 10965803
references.citation: Cancer Gene Ther. 2013 Feb;20(2):133-40
references.pmid: 23348635
references.citation: Mol Ther. 2012 Feb;20(2):287-97
references.pmid: 22031239
references.citation: J Neurovirol. 2001 Jun;7(3):208-19
references.pmid: 11517395
references.citation: Nature. 1986 Oct 30-Nov 5;323(6091):816-9
references.pmid: 3022155
references.citation: Neurobiol Aging. 2008 Nov;29(11):1744-53
references.pmid: 17543422
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12873-8
references.pmid: 16908838
references.citation: Cancer Metastasis Rev. 2006 Sep;25(3):409-16
references.pmid: 16951987
references.citation: Cancer Res. 2005 Dec 15;65(24):11255-8
references.pmid: 16357128
references.citation: Mol Ther. 2014 May;22(5):1048-55
references.pmid: 24572293
references.citation: J Gen Virol. 1980 Feb;46(2):291-300
references.pmid: 6247426
references.citation: J Immunol. 2007 Feb 15;178(4):2448-57
references.pmid: 17277152
references.citation: Mol Aspects Med. 2012 Oct-Dec;33(5-6):579-89
references.pmid: 22387049
references.citation: Am J Pathol. 1992 Mar;140(3):539-44
references.pmid: 1372154
references.citation: J Virol. 2007 Feb;81(3):1451-60
references.pmid: 17108044
references.citation: J Immunol. 2008 Nov 1;181(9):6417-26
references.pmid: 18941232
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2777-88
references.pmid: 19351762
references.citation: J Virol. 2002 Feb;76(3):1071-6
references.pmid: 11773383
references.citation: J Immunol. 2005 Oct 1;175(7):4189-93
references.pmid: 16177057
references.citation: Front Oncol. 2012 Jun 04;2:58
references.pmid: 22675673
references.citation: Mol Ther. 2007 Mar;15(3):588-97
references.pmid: 17245355
references.citation: J Infect Dis. 2007 Sep 15;196(6):853-60
references.pmid: 17703415
references.citation: Clin Cancer Res. 2008 Jan 1;14(1):259-69
references.pmid: 18172278
references.citation: Future Oncol. 2010 Jun;6(6):941-9
references.pmid: 20528232
references.citation: Mol Ther. 2008 May;16(5):879-85
references.pmid: 18388918
references.citation: J Interferon Cytokine Res. 2002 Jun;22(6):671-6
references.pmid: 12162877
references.citation: J Gen Virol. 1993 Aug;74 ( Pt 8):1527-37
references.pmid: 8345347
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Clin Cancer Res. 1999 Jun;5(6):1517-22
references.pmid: 10389941
references.citation: Neurosurgery. 2000 Apr;46(4):957-61; discussion 961-2
references.pmid: 10764271
references.citation: Mayo Clin Proc. 2014 Jul;89(7):926-33
references.pmid: 24835528
references.citation: Mol Ther. 2013 May;21(5):1014-23
references.pmid: 23481323
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3931-6
references.pmid: 9520470
references.citation: Mol Ther. 2008 Sep;16(9):1546-55
references.pmid: 18648350
references.citation: Clin Microbiol Rev. 2004 Oct;17(4):942-64, table of contents
references.pmid: 15489356
references.citation: Nat Med. 2012 Dec;18(12):1827-34
references.pmid: 23178246
references.citation: Mol Ther. 2006 Dec;14(6):779-88
references.pmid: 16996314
references.citation: J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):763-8
references.pmid: 10567494
references.citation: J Neurosurg. 1979 Mar;50(3):298-304
references.pmid: 217977
references.citation: Nature. 1986 Oct 30-Nov 5;323(6091):819-22
references.pmid: 2430188
references.citation: J Gene Med. 2007 Feb;9(2):99-106
references.pmid: 17256802
references.citation: Cell Host Microbe. 2013 Feb 13;13(2):169-80
references.pmid: 23414757
references.citation: J Neurosurg. 1979 Mar;50(3):305-11
references.pmid: 422981
references.citation: Antiviral Res. 2013 Dec;100(3):649-53
references.pmid: 24416771
references.citation: Nat Med. 1999 Aug;5(8):881-7
references.pmid: 10426310
references.citation: J Natl Cancer Inst. 2012 Jan 4;104(1):42-55
references.pmid: 22173583
references.citation: Anticancer Res. 2011 Dec;31(12):4223-30
references.pmid: 22199285
references.citation: J Pharmacol Exp Ther. 2007 Nov;323(2):488-98
references.pmid: 17704356
references.citation: Cancer Res. 2007 Oct 1;67(19):9398-406
references.pmid: 17909049
references.citation: J Neuroinflammation. 2008;5:15
references.pmid: 18477398
references.citation: J Immunol. 1999 Mar 1;162(5):2895-905
references.pmid: 10072539