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Front. Immunol. | doi: 10.3389/fimmu.2019.00002

Generation of an oncolytic herpes simplex virus 1 expressing human MelanA

Jan B. Boscheinen1, Sabrina Thomann1,  David M. Knipe2, Neal DeLuca3, Beatrice Schuler-Thurner4, Stefanie Gross4,  Jan Dörrie4,  Niels Schaft4, Christian Bach5, Anette Rohrhofer6,  Melanie Werner-Klein7,  Schmidt Barbara1, 6* and Philipp Schuster6
  • 1Abteilung für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
  • 2Department of Microbiology and Immunobiology, Harvard Medical School, United States
  • 3Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, United States
  • 4University Hospital Erlangen, Germany
  • 5Lab for Immunogenetics, Universitätsklinikum Erlangen, Germany
  • 6Institute for Medical Microbiology and Hygiene (IMHR), Germany
  • 7Regensburger Centrum für Interventionelle Immunologie (RCI), Germany

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) d106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus confirmed MelanA expression by Western blotting, flow cytometry, and immunofluorescence. HSV-1 d106S-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 confirmed 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 d106S, resulting in expression of the transgene GFP in CD11c+ cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d106S 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 d106S-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.

Keywords: Vaccine, Oncolytic virus, malignant melanoma, Herpes virus, cytotoxic T cell response

Received: 24 Aug 2018; Accepted: 02 Jan 2019.

Edited by:

Silvia B. Boscardin, University of São Paulo, Brazil

Reviewed by:

Fabian Benencia, Ohio University, United States
Andrew Zloza, Rutgers Cancer Institute of New Jersey, United States
Jurjen Tel, Eindhoven University of Technology, Netherlands  

Copyright: © 2019 Boscheinen, Thomann, Knipe, DeLuca, Schuler-Thurner, Gross, Dörrie, Schaft, Bach, Rohrhofer, Werner-Klein, Barbara and Schuster. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Schmidt Barbara, Abteilung für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bavaria, Germany, barbara.schmidt@ukr.de