title: BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy.
abstract: Purpose:Brain angiogenesis inhibitor (BAI1) facilitates phagocytosis and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here, we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV).Experimental Design:Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and Ingenuity Pathway Analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα-blocking antibodies and macrophages derived fromBai1-/-mice were used.Results:RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared with rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Furthermore, we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild-type/RAMBO virus inBai1-/-or wild-type non-tumor-bearing mice revealed the safety of this approach.Conclusions:We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety.Clin Cancer Res; 23(7); 1809-19. ©2016 AACR.
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Bolyard
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: W Hans
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Yeshavanth
authors.initials: Y
authors.lastname: Banasavadi-Siddegowda
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Jayson
authors.initials: J
authors.lastname: Hardcastle
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wohleb
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Department of Otolaryngology, Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Jun-Ge
authors.initials: JG
authors.lastname: Yu
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Samuel
authors.initials: S
authors.lastname: Dubin
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Department of Otolaryngology, Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Maninder
authors.initials: M
authors.lastname: Khosla
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Smith
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Christopher
authors.initials: C
authors.lastname: Alvarez-Breckenridge
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Pete
authors.initials: P
authors.lastname: Pow-Anpongkul
authors.affiliation: Department of Hematology, City of Hope Cancer Center, Duarte, California.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Department of Otolaryngology, Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.affiliation: Departments of Neurosurgery and Hematology and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Departments of Neurosurgery and Hematology and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio. Balveen.Kaur@osumc.edu.|The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000473:pathology; D045744:Cell Line, Tumor; D005910:Glioma / Q000235:genetics / Q000628:therapy / Q000821:virology*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000473:pathology / Q000821:virology*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D050504:Oncolytic Viruses / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D018139:Simplexvirus / Q000235:genetics / Q000472:pathogenicity; D023041:Xenograft Model Antitumor Assays
chemical_list: C468226:ADGRB1 protein, human; D042501:Angiogenic Proteins; D043562:Receptors, G-Protein-Coupled