Boscheinen, Jan B. and Thomann, Sabrina and Knipe, David M. and DeLuca, Neal and Schuler-Thurner, Beatrice and Gross, Stefanie and Dorrie, Jan and Schaft, Niels and Bach, Christian and Rohrhofer, Anette and Werner-Klein, Melanie and Schmidt, Barbara and Schuster, Philipp (2019) Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA. FRONTIERS IN IMMUNOLOGY, 10: 2. ISSN 1664-3224,
Full text not available from this repository. (Request a copy)Abstract
Robust anti-tumor immunity requires innate as well as adaptive immune responses. We have shown that plasmacytoid dendritic cells develop killer cell-like activity in melanoma cell cocultures after exposure to the infectious but replication-deficient herpes simplex virus 1 (HSV-1) d 106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d 106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus con firmed MelanA expression by Western blotting, flow cytometry, and immuno fluorescence. HSV-1 d 106S-MelanA induced expression of the transgene in fibroblast and melanoma cell lines not naturally expressing MelanA. Infection of a melanoma cell line with CRISPR-Cas9-mediated knockout of MelanA con firmed de novo expression of the transgene in the viral context. Dependent on MelanA expression, infected fibroblast and melanoma cell lines induced degranulation of HLA-matched MelanA-specific CD8(+) T cells, followed by killing of infected cells. To study infection of immune cells, we exposed peripheral blood mononuclear cells and in vitro-differentiated macrophages to the parental HSV-1 d 106S, resulting in expression of the transgene GFP in CD11c(+) cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d 106S could enhance adaptive immune responses and re-direct MelanA-specific CD8(+) T cells to tumor lesions, which have escaped adaptive immune responses via downregulation of their tumor antigen. Hence, HSV-1 d 106S-MelanA harbors the potential to induce innate immune responses in conjunction with adaptive anti-tumor responses by CD8(+) T cells, which should be evaluated in further studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PLASMACYTOID DENDRITIC CELLS; CYTOTOXIC T-LYMPHOCYTES; IMMUNE-RESPONSES; LYMPH-NODES; ANTIGEN; VACCINE; IDENTIFICATION; MONOCYTES; GENOME; TYPE-1; vaccine; oncolytic viruses; malignant melanoma; herpes virus; cytotoxic T cell response |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Apr 2020 07:09 |
| Last Modified: | 27 Apr 2020 07:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27713 |
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