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Clin Cancer Res. 2017 Apr 1;23(7):1809-1819. doi: 10.1158/1078-0432.CCR-16-1818. Epub 2016 Nov 9.

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy.

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Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Department of Otolaryngology, Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
Department of Hematology, City of Hope Cancer Center, Duarte, California.
Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio.
Departments of Neurosurgery and Hematology and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia.
Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.


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 from Bai1-/- 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 in Bai1-/- 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.

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