Background: Neuroblastoma is an aggressive paediatric tumor and highly resistant to the current therapeutic approaches. Here we proposed a new treatment strategy by using an engineered anaerobe Salmonella (Sal-YB1).
Method: Nude and NOD-SCID mice were used in the intra-adrenal orthotopic neuroblastoma mouse models. They were divided into no intervention and Sal-YB1 treated arms. Sal-YB1 was administered through the tail vein. The therapeutic effectiveness, biosafety and related mechanism were studied.
Results: No mice from treatment and control arms died of treatment. Tumor regression rate was 70% in nude mice and 30% in NOD-SCID mice; and the treatment effect was significantly different (P < 0.05). Salmonella could not be detected in urine; 75% mice had Sal-YB1 found in stool initially but they all turned negative within two weeks. Tumor tissues had a relatively higher Sal-YB1 positive rate and necrotic change in Sal-YB1 treated mice. It was significant difference for IRAK (P < 0.05) and IkBα (P < 0.001) in the tumor mass between YB1-treated & -untreated group. Sal-YB1 could significantly up-regulate TLR4 expression in YB1-treated tumor samples (P < 0.001). There were higher release of TNFα found in macrophage and mouse tumor tissue with Sal-YB1 treatment (P < 0.05). Neuroblastoma cells supplemented with the supernatant of Sal-YB1 pre-treated macrophage revealed significantly higher cell death (P < 0.05). TNFα and pan-Caspase inhibitors could reverse the anti-neuroblastoma effect by macrophage (P < 0.001).
Conclusion: Our approach provides a new paradigm in treaating neuroblastoma. The macrophages may play a critical role in Sal-YB1 directed therapy.