title: Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy.
abstract: OBJECTIVE
  Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)-expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy.
  
  
  METHODS
  Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA-targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou-Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy.
  
  
  RESULTS
  Combination treatment with bortezomib- and oHSV-induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy.
  
  
  CONCLUSIONS
  This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients. Clin Cancer Res; 22(21); 5265-76. ©2016 AACRSee related commentary by Suryadevara et al., p. 5164.
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio. balveen.kaur@osumc.edu Jiyoung.Yoo@osumc.edu.
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.
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Bolyard
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Department of Chemistry and Biochemistry, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Department of Microbiology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Nallanagulagari
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Neuroscience Graduate Studies Program, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Department of Biomedical Science Major, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Hurwitz
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Medical Scientist Training Program, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Theresa
authors.initials: T
authors.lastname: Relation
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: Departments of Surgery, Immunology, and Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Jun-Ge
authors.initials: JG
authors.lastname: Yu
authors.affiliation: Department of Biomedical Informatics, Center for Biostatistics, James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.
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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio. balveen.kaur@osumc.edu Jiyoung.Yoo@osumc.edu.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
mesh_terms: D000818:Animals; D000069286:Bortezomib / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017382:Reactive Oxygen Species; D000069286:Bortezomib; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053179:Caspase 7