Blockage of autophagy pathway enhances Salmonella tumor-targeting

Previous studies have shown that strains of Salmonella typhimurium specifically target tumors in mouse models of cancer. In this study, we report that tumor-targeting Salmonella typhimurium A1-R (A1-R) or VNP20009 induced autophagy in human cancer cells, which serves as a defense response. Functionally, by knockdown of essential autophagy genes Atg5 or Beclin1 in bacteria-infected cancer cells, the autophagy pathway was blocked, which led to a significant increase of intracellular bacteria multiplication in cancer cells. Genetic inactivation of the autophagy pathway enhanced A1-R or VNP20009-mediated cancer cell killing by increasing apoptotic activity. We also demonstrate that the combination of pharmacological autophagy inhibitors chloroquine (CQ) or bafilomycin A1 (Baf A1) with tumor-targeting A1-R or VNP20009 significantly enhanced cancer-cell killing compared with Salmonella infection alone. These findings provide a proof-of-concept of combining autophagy inhibitors and tumor-targeting Salmonella to enhance cancer-cell killing.