Microglia and astrocytes attenuate the replication of the oncolytic vaccinia virus LIVP 1.1.1 in murine GL261 gliomas by acting as vaccinia virus traps

Journal of Translational Medicine

Aladar A Szalay³  Nanhai G Chen³  Ulrike Geissinger³  Stephanie Weibel²  Susanne Rohn¹  Christina Kober¹ 

[1] Department of Biochemistry, Biocenter, University of Wuerzburg, Am Hubland, Würzburg, 97074, Germany;Department of Anesthesia and Critical Care, University Hospital of Wuerzburg, Oberduerrbacher Str. 6, Würzburg, 97080, Germany;Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, San Diego 92109, CA, USA

关键词: OSC;    IMA2.1;    BV-2;    Tumor microenvironment;    Microglia;    Polarization;    VACV;    GBM;   

Others  :  1221472
DOI  :  10.1186/s12967-015-0586-x

 received in 2015-01-14, accepted in 2015-06-25,  发布年份 2015

【 摘 要 】

Background

Oncolytic virotherapy is a novel approach for the treatment of glioblastoma multiforme (GBM) which is still a fatal disease. Pathologic features of GBM are characterized by the infiltration with microglia/macrophages and a strong interaction between immune- and glioma cells. The aim of this study was to determine the role of microglia and astrocytes for oncolytic vaccinia virus (VACV) therapy of GBM.

Methods

VACV LIVP 1.1.1 replication in C57BL/6 and Foxn1 ^nu/numice with and without GL261 gliomas was analyzed. Furthermore, immunohistochemical analysis of microglia and astrocytes was investigated in non-, mock-, and LIVP 1.1.1-infected orthotopic GL261 gliomas in C57BL/6 mice. In cell culture studies virus replication and virus-mediated cell death of GL261 glioma cells was examined, as well as in BV-2 microglia and IMA2.1 astrocytes with M1 or M2 phenotypes. Co-culture experiments between BV-2 and GL261 cells and apoptosis/necrosis studies were performed. Organotypic slice cultures with implanted GL261 tumor spheres were used as additional cell culture system.

Results

We discovered that orthotopic GL261 gliomas upon intracranial virus delivery did not support replication of LIVP 1.1.1, similar to VACV-infected brains without gliomas. In addition, recruitment of Iba1 ⁺microglia and GFAP ⁺astrocytes to orthotopically implanted GL261 glioma sites occurred already without virus injection. GL261 cells in culture showed high virus replication, while replication in BV-2 and IMA2.1 cells was barely detectable. The reduced viral replication in BV-2 cells might be due to rapid VACV-induced apoptotic cell death. In BV-2 and IMA 2.1 cells with M1 phenotype a further reduction of virus progeny and virus-mediated cell death was detected. Application of BV-2 microglial cells with M1 phenotype onto organotypic slice cultures with implanted GL261 gliomas resulted in reduced infection of BV-2 cells, whereas GL261 cells were well infected.

Conclusion

Our results indicate that microglia and astrocytes, dependent on their activation state, may preferentially clear viral particles by immediate uptake after delivery. By acting as VACV traps they further reduce efficient virus infection of the tumor cells. These findings demonstrate that glia cells need to be taken into account for successful GBM therapy development.

【 授权许可】

   
2015 Kober et al.

【 图 表 】

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