title: Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling.
abstract: BACKGROUND
  Systemic delivery of a complementary cDNA library expressed from the vesicular stomatitis virus (VSV) treats tumors by vaccinating against a wide range of tumor associated antigens (TAAs). For subcutaneous B16 melanomas, therapy was achieved using a specific combination of self-TAAs (neuroblastoma-Ras, cytochrome c, and tyrosinase-related protein 1) expressed from VSV. However, for intracranial B16 tumors, a different combination was therapeutic (consisting of VSV-expressed hypoxia-inducible factor [HIF]-2α, Sox-10, c-Myc, and tyrosinase-related protein 1). Therefore, we tested the hypothesis that tumors of different histological types growing in the brain share a common immunogenic signature which can be exploited for immunotherapy.
  
  
  METHODS
  Syngeneic tumors, including GL261 gliomas, in the brains of immune competent mice were analyzed for their antigenic profiles or were treated with systemic viroimmunotherapy.
  
  
  RESULTS
  Several different histological types of tumors growing intracranially, as well as freshly resected human brain tumor explants, expressed a HIF-2α(Hi) phenotype imposed by brain-derived CD11b+ cells. This location-specific antigen expression was exploited therapeutically against intracranial GL261 gliomas using systemically delivered VSV expressing HIF-2α, Sox-10, and c-Myc. Viroimmunotherapy was enhanced by immune checkpoint inhibitors, associated with the de-repression of antitumor T-helper cell type 1 (Th1) interferon-γ and Th17 T cell responses.
  
  
  CONCLUSIONS
  Since different tumor types growing in the same location in the brain share a location-specific phenotype, we suggest that antigen-specific immunotherapies should be based upon expression of both histological type-specific tumor antigens and location-specific antigens. Our findings support clinical application of VSV-TAA therapy with checkpoint inhibition for aggressive brain tumors and highlight the importance of the intracranial microenvironment in sculpting a location-specific profile of tumor antigen expression.
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Julia V
authors.initials: JV
authors.lastname: Cockle
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Karishma
authors.initials: K
authors.lastname: Rajani
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Kottke
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Diaz
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Shim
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Tim
authors.initials: T
authors.lastname: Peterson
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Ian F
authors.initials: IF
authors.lastname: Parney
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Susan
authors.initials: S
authors.lastname: Short
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ilett
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.); Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.); Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.); Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.).
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints / Q000276:immunology*; D003131:Combined Modality Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy; D014407:Tumor Cells, Cultured; D018116:Vesiculovirus / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D007371:Interferon-gamma
keywords: cancer immunotherapy; checkpoint inhibitor; glioma; oncolytic virus; vesicular stomatitis virus