title: Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus.
abstract: Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Alberta, Canada. Clark H. Smith Brain Tumor Center, University of Calgary, Alberta, Canada.
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Alberta, Canada. Clark H. Smith Brain Tumor Center, University of Calgary, Alberta, Canada.
authors.forename: Brienne A
authors.initials: BA
authors.lastname: McKenzie
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Alberta, Canada. Clark H. Smith Brain Tumor Center, University of Calgary, Alberta, Canada.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.affiliation: Mouse Cancer Genetics Program, NCI, Frederick, Maryland.
authors.forename: Karlyne M
authors.initials: KM
authors.lastname: Reilly
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.affiliation: Hotchkiss Brain Institute, Departments of Clinical Neurosciences, University of Calgary, Alberta, Canada. Hotchkiss Brain Institute, Department of Oncology, University of Calgary, Alberta, Canada.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Alberta, Canada. Clark H. Smith Brain Tumor Center, University of Calgary, Alberta, Canada. Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute and University of Southern Florida, Tampa, Florida. Peter.Forsyth@moffitt.org.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009233:Myxoma virus / Q000276:immunology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D003520:Cyclophosphamide; D020123:Sirolimus