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Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro
Oncolytic virus (OV) therapy is an emerging approach with the potential to redefine treatment options across a range of cancer indications and in patients who remain resistant to existing standards of care, including immuno-oncology (IO) drugs. MEDI5395, a recombinant Newcastle disease virus (NDV),...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230062/ https://www.ncbi.nlm.nih.gov/pubmed/32088771 http://dx.doi.org/10.1007/s00262-020-02495-x |
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author | Burke, Shannon Shergold, Amy Elder, Matthew J. Whitworth, Justine Cheng, Xing Jin, Hong Wilkinson, Robert W. Harper, James Carroll, Danielle K. |
author_facet | Burke, Shannon Shergold, Amy Elder, Matthew J. Whitworth, Justine Cheng, Xing Jin, Hong Wilkinson, Robert W. Harper, James Carroll, Danielle K. |
author_sort | Burke, Shannon |
collection | PubMed |
description | Oncolytic virus (OV) therapy is an emerging approach with the potential to redefine treatment options across a range of cancer indications and in patients who remain resistant to existing standards of care, including immuno-oncology (IO) drugs. MEDI5395, a recombinant Newcastle disease virus (NDV), engineered to express granulocyte–macrophage colony-stimulating factor (GM-CSF), exhibits potent oncolytic activity. It was hypothesized that activation of immune cells by MEDI5395, coupled with its oncolytic activity, would enhance the priming of antitumor immunity. Using MEDI5395 and recombinant NDVs encoding fluorescent reporter genes, we demonstrated preferential virus uptake and non-productive infection in myeloid cells, including monocytes, macrophages, and dendritic cells (DCs). Infection resulted in immune-cell activation, with upregulation of cell surface activation markers (e.g., CD80, PD-L1, HLA-DR) and secretion of proinflammatory cytokines (IFN-α2a, IL-6, IL-8, TNF-α). Interestingly, in vitro M2-polarized macrophages were more permissive to virus infection than were M1-polarized macrophages. In a co-culture system, infected myeloid cells were effective virus vectors and mediated the transfer of infectious NDV particles to tumor cells, resulting in cell death. Furthermore, NDV-infected DCs stimulated greater proliferation of allogeneic T cells than uninfected DCs. Antigens released after NDV-induced tumor cell lysis were cross-presented by DCs and drove activation of tumor antigen-specific autologous T cells. MEDI5395 therefore exhibited potent immunostimulatory activity and an ability to enhance antigen-specific T-cell priming. This, coupled with its tumor-selective oncolytic capacity, underscores the promise of MEDI5395 as a multimodal therapeutic, with potential to both enhance current responding patient populations and elicit de novo responses in resistant patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-020-02495-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7230062 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-72300622020-05-18 Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro Burke, Shannon Shergold, Amy Elder, Matthew J. Whitworth, Justine Cheng, Xing Jin, Hong Wilkinson, Robert W. Harper, James Carroll, Danielle K. Cancer Immunol Immunother Original Article Oncolytic virus (OV) therapy is an emerging approach with the potential to redefine treatment options across a range of cancer indications and in patients who remain resistant to existing standards of care, including immuno-oncology (IO) drugs. MEDI5395, a recombinant Newcastle disease virus (NDV), engineered to express granulocyte–macrophage colony-stimulating factor (GM-CSF), exhibits potent oncolytic activity. It was hypothesized that activation of immune cells by MEDI5395, coupled with its oncolytic activity, would enhance the priming of antitumor immunity. Using MEDI5395 and recombinant NDVs encoding fluorescent reporter genes, we demonstrated preferential virus uptake and non-productive infection in myeloid cells, including monocytes, macrophages, and dendritic cells (DCs). Infection resulted in immune-cell activation, with upregulation of cell surface activation markers (e.g., CD80, PD-L1, HLA-DR) and secretion of proinflammatory cytokines (IFN-α2a, IL-6, IL-8, TNF-α). Interestingly, in vitro M2-polarized macrophages were more permissive to virus infection than were M1-polarized macrophages. In a co-culture system, infected myeloid cells were effective virus vectors and mediated the transfer of infectious NDV particles to tumor cells, resulting in cell death. Furthermore, NDV-infected DCs stimulated greater proliferation of allogeneic T cells than uninfected DCs. Antigens released after NDV-induced tumor cell lysis were cross-presented by DCs and drove activation of tumor antigen-specific autologous T cells. MEDI5395 therefore exhibited potent immunostimulatory activity and an ability to enhance antigen-specific T-cell priming. This, coupled with its tumor-selective oncolytic capacity, underscores the promise of MEDI5395 as a multimodal therapeutic, with potential to both enhance current responding patient populations and elicit de novo responses in resistant patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-020-02495-x) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-02-22 2020 /pmc/articles/PMC7230062/ /pubmed/32088771 http://dx.doi.org/10.1007/s00262-020-02495-x Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Article Burke, Shannon Shergold, Amy Elder, Matthew J. Whitworth, Justine Cheng, Xing Jin, Hong Wilkinson, Robert W. Harper, James Carroll, Danielle K. Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
title | Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
title_full | Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
title_fullStr | Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
title_full_unstemmed | Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
title_short | Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
title_sort | oncolytic newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230062/ https://www.ncbi.nlm.nih.gov/pubmed/32088771 http://dx.doi.org/10.1007/s00262-020-02495-x |
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