NDLI: VSTAT120 REDUCES THE INNATE INFLAMMATORY RESPONSE TO INFECTION AND ENHANCES ONCOLYTIC VIRAL THERAPY FOR GLIOBLASTOMA

Content Provider	PubMed Central
Author	Kaur, Balveen Meisen, W. Hans Hardcastle, Jayson Jeffrey, Wojton Wohleb, Eric Christopher, Alvarez-breckenridge Pete, Pow-anpongkul Godbout, Jonathan
Copyright Year	2014
Abstract	BACKGROUND: A major barrier to oncolytic virus (OV) efficacy for the treatment of Glioblastoma is the innate immune response; this response limits virus replication and reduces tumor cell destruction. Our lab developed a novel OV, RAMBO, which expresses the anti-angiogenic fragment Vasculostatin (Vstat120). In addition to its anti-angiogenic effects, we observe the RAMBO virus replicates more efficiently and persists longer in vivo than a control virus (rHSVQ1). The primary objective of this study is to investigate the effects RAMBO directed Vstat120 expression on microglia/macrophage activation and OV efficacy. METHODS: Mice bearing intracranial tumors were treated with RAMBO, rHSVQ1, or PBS, and flow cytometry utilized to examine monocyte/microglia activation/recruitment. Coculture of i9nfected glioma cells with microglia were utilized in in vitro experiemnts. Cytokines were analyzed via qPCR and ELISA. Virus replication was determined by plaque forming unit (PFU) assays. RESULTS: Treatment of intracranial tumors with OV resulted in significant monocyte infiltration into the tumor. Surprisingly, this infiltration was reduced 4.5 fold in tumors treated with the RAMBO virus as compared to rHSVQ1 (p < 0.05). Infiltrating monocytes from RAMBO treated tumors had significantly less MHCII, Ly6C, and CD86 than rHSVQ1 treated tumors (p < 0.05). The microglia of RAMBO treated tumors had significantly less MHCII and CD206 expression than those treated with rHSVQ1 (p< 0.05). To further examine the interaction of Vstat120 with microglia/monocytes we developed a coculture system with murine microglia and infected human glioma cells. Glioma cells were treated with PBS, rHSVQ1, or RAMBO and cocultured with microglia. We observed a 75-fold induction of TNF-α expression in microglia cultured with rHSVQ1 infected glioma cells compared to untreated microglia (p < 0.05). Interestingly, we observed a 3.4-fold reduction in microglia TNF-α expression in RAMBO treated cocultures compared to rHSVQ1 cocultures (p < 0.01). Consistent with this ELISA confirmed a 6.9 fold decrease in microglia TNF-α secretion (p < 0.01), and virus titers revealed a 2.6 fold increase in infectious virus in RAMBO Vs eHSVQ1 treated cocultures (p < 0.01). Cocultures treated with a microglia (murine) specific TNF-α blocking antibody rescued the differences in viral replication between rHSVQ1 and RAMBO virus titers. There was no difference in virus replication of glioma cells or microglia alone. These results suggest Vstat120 reduces inflammation and enhances OV replication in part through the suppression of TNF-α expression/secretion on microglia/monocytes. This transient suppression of the microglia/monocyte inflammatory response enhances OV replication and promotes anti-tumor efficacy. CONCLUSIONS: Vasculostatin affects macrophage recruitment and activity to improve viral replication and efficacy. SECONDARY CATEGORY: Immunobiology & Immunotherapy.
Related Links	http://dx.doi.org/10.1093/neuonc/nou209.2
Starting Page	42
File Format	PDF
ISSN	15235866
e-ISSN	15235866
Journal	Neuro-Oncology
Issue Number	Suppl 3
Volume Number	16
Language	English
Publisher	Oxford University Press
Publisher Date	2014-07-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Neurology (clinical) Oncology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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