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Author Notes:

Dr. Balveen Kaur, Department of Neurological Surgery, The Ohio State University, 385-DOSUCCC, 410 West 12th Avenue Columbus, OH 43210.Tel: 614-292-3984. Fax: 614-688-4882. Balveen.Kaur@osumc.edu.

Conception and design: C. Bolyard, W.H. Meisen, C. Alvarez-Breckenridge, P. Pow-anpongkul, M.A. Caligiuri, J. Yu, B. Kaur

Development of methodology: C. Bolyard, W.H. Meisen, Y. Banasavadi-Siddegowda, J. Hardcastle, J.Y. Yoo, E.S. Wohleb, J.-G. Yu, C. Alvarez-Breckenridge, P. Pow-anpongkul, F. Pichiorri, J.P. Godbout

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C. Bolyard, W.H. Meisen, Y. Banasavadi-Siddegowda, J. Hardcastle, J.Y. Yoo, E.S. Wohleb, J. Wojton, J.-G. Yu, S. Dubin, J. Smith, M. Old, D. Zhu, E.G. Van Meir, J.P. Godbout

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C. Bolyard, W.H. Meisen, Y. Banasavadi-Siddegowda, J. Hardcastle, J.Y. Yoo, J. Wojton, M. Khosla, P. Pow-anpongkul, J. Zhang, E.G. Van Meir, J.P. Godbout, M.A. Caligiuri

Writing, review, and/or revision of the manuscript: C. Bolyard, W.H. Meisen, E.S. Wohleb, M. Old, E.G. Van Meir, J.P. Godbout, J. Yu, B. Kaur

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C. Bolyard, B. Xu

Study supervision: C. Bolyard, M. Old, M.A. Caligiuri, J. Yu, B. Kaur

We would like to acknowledge the Analytical Cytometry Shared Resource, the Center for Biostatistics, and the Target Validation Shared Resources within the James Comprehensive Cancer Center, all at The Ohio State University, for their services

We also acknowledge creative commons (https://creativecommons.org/licenses/by/3.0/) whose material was used to create cartoons in Figure 2.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We would like to acknowledge the Analytical Cytometry Shared Resource, the Center for Biostatistics, and the Target Validation Shared Resources within the James Comprehensive Cancer Center, all at The Ohio State University, for their services.

E.G. Van Meir is listed as a co-inventor on a patent, which is owned by Emory University, on method of treating abnormal angiogenesis via the BAI family of proteins and their protein fragments.

No potential conflicts of interest were disclosed by the other authors.

Subjects:

Research Funding:

This work is supported in part by: NIH grants R01NS064607, R01CA150153, P30NS045758 (to BK); P01CA163205 (to BK and MC), Pelotonia Fellowship to S. Dubin; T32CA009338 (to CB), IRG-67-003-50 (to JYY), P30CA016058 (to MC and BK), R01NS096236, P30CA138292, the Southeastern Brain Tumor Foundation (to EGVM) and the CURE Childhood Cancer and St. Baldrick’s Foundations (to EGVM and DZ).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • HERPES-SIMPLEX-VIRUS
  • BRAIN ANGIOGENESIS INHIBITOR-1
  • GRAM-NEGATIVE BACTERIA
  • ANTITUMOR EFFICACY
  • TNF-ALPHA
  • IN-VIVO
  • ENGULFMENT RECEPTOR
  • SICKNESS BEHAVIOR
  • APOPTOTIC CELLS
  • PROTEIN CCN1

BAI1 orchestrates macrophage inflammatory response to HSV infection- implications for oncolytic viral therapy

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Journal Title:

Clinical Cancer Research

Volume:

Volume 23, Number 7

Publisher:

, Pages 1809-1819

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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 microgliawas 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 andmacrophages 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.

Copyright information:

© 2016 American Association for Cancer Research.

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