title: Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance.
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.
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Amy Haseley
authors.initials: AH
authors.lastname: Thorne
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Russell
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Bolyard
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Rich
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Puduvalli
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D005909:Glioblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D050504:Oncolytic Viruses / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D055515:Cysteine-Rich Protein 61