Mesenchymal stem cell carriers enhance antitumor efficacy induced by oncolytic reovirus in acute myeloid leukemia.

Abstract

Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the therapeutic efficacy is modest, and most commonly manifests as relapse from remission. Thus, improving long-term AML survival is a crucial clinical challenge. In recent years, oncolytic virotherapy has provided an alternative approach for AML treatment. The use of oncolytic reoviruses has been explored in more than 30 clinical trials for safety and feasibility issues. However, like other oncolytic viruses, neutralizing antibodies (NAbs) reduce therapeutic efficacy. To tackle this problem, human umbilical cord mesenchymal stem cells (hUC-MSCs) were used to deliver reovirus using in vitro and in vivo models. Human UC-MSCs were successfully loaded with reovirus, without impairing biological function.We also observed in vitro protective effects of hUC-MSCs on reovirus in the presence of NAbs. In the immunocompromised AML mouse model, hUC-MSCs effectively carried reoviruses to tumor lesions and significantly prolonged the survival of AML xenografts in mice in the presence of a high titer anti-reovirus antibody (p = 0.001). However, reovirus-induced activation of AKT, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and NF-κB signaling led to the maintenance of intrinsic migratory properties and secretion of pro-inflammatory cytokines from hUC-MSCs, particularly CXCL10. In immuno-competent AML mice, MSCs carrying reovirus triggered immune responses, and eventually inhibited tumor growth. Therefore, these results suggest that MSCs as carriers of oncolytic reoviruses can enhance the antitumor efficacy of virotherapy.

• Authors: Xianyao Wang, Yichen Yang, Nianxue Wang, Xijun Wu, Jianwei Xu, Yanhua Zhou, Xing Zhao, Zhixu He
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 94 Pg. 107437 (May 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 33571747 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Topics

• Animals
• Cell Line
• Female
• Humans
• Leukemia, Myeloid, Acute (therapy)
• Mesenchymal Stem Cells
• Oncolytic Virotherapy
• Oncolytic Viruses