Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor

Background: Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far.Methods: The anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors.Results: We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFN gamma and CCL2 were elevated in the liver after YB1 administration, but only IFN gamma was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFN gamma caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis.Conclusion: We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFN gamma induction. Targeted IFN gamma therapy can replace YB1 for treating liver metastasis of PNETs.

Automated summary

This study demonstrated that genetically engineered tumor-targeting Salmonella typhimurium YB1 may exhibit anti-tumor effect mainly based on the induction of IFN gamma, and targeted IFN gamma therapy can replace YB1 for treating liver metastasis of pancreatic neuroendocrine tumors (PNETs).