Oncolytic Newcastle disease virus delivered by Mesenchymal stem cells-engineered system enhances the therapeutic effects altering tumor microenvironment

Mohsen Keshavarz,Hassan Dianat-Moghadam,Seyedeh Sara Ghorbanhosseini,Amir Ghaemi,Hossein Keyvani,Seyed Reza Mohebbi,Mir Saeed Ebrahimzadeh,Seyed Mohammad Miri

doi:10.1186/s12985-020-01326-w

Abstract

BackgroundHuman papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women. Cancer immunotherapy has represented great potential as a new promising cancer therapeutic approach. Here, we report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor.MethodsFor this purpose, MSCs obtained from the bone marrow of C57BL mice, then cultured and characterized subsequently by the flow cytometry analysis for the presence of cell surface markers. In this study, we sought out to determine the impacts of MSCs loaded with oncolytic NDV on splenic T cell and cytokine immune responses, caspase-3 and -9 expression, and myeloid and myeloid-derived suppressor cells (MDSCs) by histological and immunohistochemical studies in the tumor microenvironment (TME).ResultsOur findings proved that MSCs possess both migratory capacity and tumor tropism toward transplanted tumor tissue after peritumoral administration. Tumor therapy experiments indicated that oncolytic NDV delivered by MSCs-engineered system significantly reduces tumor growth, which is associated with the enhancement of E7-specific lymphocyte proliferation, CD8+ T cell cytolysis responses, and splenic IFN-γ, IL-4 and IL-12 responses compared with control groups. Moreover, the treatment upregulated the concentration of apoptotic proteins (caspase 9) and increased infiltration of tumor microenvironment with CD11b + myeloid and Gr1 + MDSCs cells.ConclusionsOur data suggest MSCs carrying oncolytic NDV as a potentially effective strategy for cancer immunotherapy through inducing splenic Th1 immune responses and apoptosis in the tumor microenvironment.

Highlights

Human papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women
The analyses showed that the majority of BM-Mesenchymal stem cells (MSCs) expressed high levels of CD44 (94.8%) and CD105 (91.7%) cell surface markers
Compared with the mild anti-tumoral effect of MSC/ Inactivated Newcastle disease virus (iNDV) and iNDV groups, active Newcastle disease virus (NDV) and NDV-loaded MSCs can remarkably reduce tumor volume by comparison with the MSC and PBS control (p < 0.0001). These results demonstrate that treatment with 108 pfu active NDV alone or engulfed by MSC (~ 2 × 106 NDV particles) promotes a strong immune response, which can turn into an anti-tumor response

Summary

Introduction

Human papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women. We report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor. Human papillomavirus (HPV) is one of the most usual reproductive tract viral infection that accounts for approximately 90% of cervical and anal carcinomas and 60% of oropharyngeal cancer [1]. Human papillomavirus (HPV) 16 and 18 are two types of high-risk HPV associated with most malignancy. Cancer cells with high replicative activity, their deficiencies in antiviral type I interferon signaling, and cell surface overexpression of receptors-mediated cellular entry of virus [6], all provide the opportunity to employ oncolytic viruses (OVs) as a novel tool for cancer therapy. OVs can selectively infect and kill tumor cells while leaving normal cells intact [7]

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