title: TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response.
abstract: Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFβ, might reverse these effects and thereby potentiate oHSV efficacy. TGFβ treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFβ treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFβ prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFβ prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFβ prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes.
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Han
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Xilin
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Lichao
authors.initials: L
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Radiology, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School, Boston, Massachusetts.
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Department of Neurological Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. jianhua.yu@osumc.edu.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005909:Glioblastoma / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta