Salmonella-based cancer immunotherapy relies on tumor metabolic changes

Abstract

Microbe-based treatments have become a promising strategy in the fight of cancer. The rationale behind the anti-tumor potential relies on its direct action against tumor cells, and also on its highly immunogenic nature, skewing the tumor microenvironment to an anti-tumorigenic phenotype. Our group has been extensively investigating attenuated Salmonella enterica serovar Typhimurium, particularly LVR01 (aroC-) strain, as a candidate for cancer immunotherapy, as it has also shown exerting direct and indirect effects against tumor cells in different cancer models. In this work we report that the expression of several molecules related to energy production, metabolism and cell proliferation is modified by Salmonella LVR01 treatment. First, we performed metabolomics on tumor samples, showing a general profile of reduced availability of several aminoacids and TCA-related organic acids in Salmonella-treated tumors, which could explain tumor growth retardation due to reduced energy availability. Moreover, through comparative mass spectrometry we detected a rapid increase in proteins involved in aminoacid metabolism as malate dehydrogenase and asparagine synthetase, and others related to glucose or lipid metabolism, as phosphoglucomutase-1 and fatty acyl-CoA reductase 1, respectively. Accordingly, some of these enzymes have shown significant cancer associations, reinforcing our results. Moreover, the use of 2-deoxyglucose, a glycolysis inhibitor, prior to Salmonella infection of melanoma cells, showed to partially revert the phenotype, opening new questions about the pathways induced with both treatments. All in all, our preliminary results point out to a scenario where energy and nutrient depletion by Salmonella is at the center of antitumor activity. While this work is currently in a descriptive stage, ongoing in vivo experiments using 2-deoxyglucose in tumor bearing mice may further clarify the relevance of tumor metabolism in the context of the therapy.