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- Title
Role of Cysteine-rich 61 Protein (CCN1) in Macrophage-mediated Oncolytic Herpes Simplex Virus Clearance.
- Authors
Thorne, Amy Haseley; Meisen, Walter H; Russell, Luke; Yoo, Ji Young; Bolyard, Chelsea M; Lathia, Justin D; Rich, Jeremy; Puduvalli, Vinay K; Mao, Hsiaoyin; Yu, Jianhua; Caligiuri, Michael A; Tridandapani, Susheela; Kaur, Balveen
- Abstract
Glioblastoma is a devastating disease, and there is an urgent need to develop novel therapies, such as oncolytic HSV1 (OV) to effectively target tumor cells. OV therapy depends on tumor-specific replication leading to destruction of neoplastic tissues. Host responses that curtail virus replication limit its efficacy in vivo. We have previously shown that cysteine-rich 61 protein (CCN1) activates a type 1 IFN antiviral defense response in glioblastoma cells. Incorporating TCGA data, we found CCN1 expression to be a negative prognostic factor for glioblastoma patients. Based on this, we used neutralizing antibodies against CCN1 to investigate its effect on OV therapy. Use of an anti-CCN1 antibody in mice bearing glioblastomas treated with OV led to enhanced virus expression along with reduced immune cell infiltration. OV-induced CCN1 increases macrophage migration toward infected glioblastoma cells by directly binding macrophages and also by enhancing the proinflammatory activation of macrophages inducing MCP-1 expression in glioblastoma cells. Activation of macrophages by CCN1 also increases viral clearance. Neutralization of integrin αMβ2 reversed CCN1-induced macrophage activation and migration, and reduced MCP-1 expression by glioblastoma cells. Our findings reveal that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors.
- Subjects
CYSTEINE; HERPES simplex treatment; HERPES simplex virus; GLIOBLASTOMA multiforme treatment; CANCER cells; MACROPHAGES
- Publication
Molecular Therapy, 2014, Vol 22, Issue 9, p1678
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2014.101