Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling
| Autor: | Alan Melcher, Richard G. Vile, Jill Thompson, Timothy Kottke, Rosa Maria Diaz, Timothy E. Peterson, Kevin G. Shim, Peter Selby, Karishma Rajani, Ian F. Parney, Elizabeth Ilett, Susan C Short, Shane Zaidi, Julia V. Cockle |
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| Rok vydání: | 2015 |
| Předmět: |
Male
0301 basic medicine Cancer Research Cell cycle checkpoint medicine.medical_treatment Melanoma Experimental Brain tumor Enzyme-Linked Immunosorbent Assay Biology Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Immune system Antigen Cancer immunotherapy Antigens Neoplasm Glioma Tumor Cells Cultured medicine Animals Humans Oncolytic Virotherapy Mice Inbred C3H Brain Neoplasms Cell Cycle Cell Cycle Checkpoints Vesiculovirus Immunotherapy Flow Cytometry medicine.disease Combined Modality Therapy Xenograft Model Antitumor Assays Tumor antigen Mice Inbred C57BL 030104 developmental biology Oncology 030220 oncology & carcinogenesis Basic and Translational Investigations Immunology Cancer research Neurology (clinical) |
| Zdroj: | Neuro-Oncology. 18:518-527 |
| ISSN: | 1523-5866 1522-8517 |
| Popis: | 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-2αHi 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. |
| Databáze: | OpenAIRE |
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