Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro
Autor: | Amy Shergold, Shannon Burke, Robert W. Wilkinson, Matthew J. Elder, Hong Jin, Justine Whitworth, James Harper, Danielle Carroll, Xing Cheng |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Oncolytic Newcastle Disease Virus
MEDI5395 Cancer Research Oncolytic virus medicine.medical_treatment Immunology Genetic Vectors Newcastle disease virus Biology Virus 03 medical and health sciences 0302 clinical medicine Immune system Antigen Cell Line Tumor medicine Immunology and Allergy Humans 030304 developmental biology Oncolytic Virotherapy 0303 health sciences Innate immune system Immunotherapy Immunity Innate Oncolytic Viruses Oncology 030220 oncology & carcinogenesis Cancer research Original Article CD80 |
Zdroj: | Cancer Immunology, Immunotherapy |
ISSN: | 1432-0851 0340-7004 |
Popis: | 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. |
Databáze: | OpenAIRE |
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