Tumor Colonization and Therapy by Escherichia coli Nissle 1917 Strain in Syngeneic Tumor-Bearing Mice Is Strongly Affected by the Gut Microbiome

SIMPLE SUMMARY: Cancer is a leading cause of disease-related death in humans and in domestic animals. Despite recent progress in the diagnosis and treatment of advanced cancer, the overall patient treatment outcome did not substantially improve. Bacterium-mediated cancer therapy is one promising method of cancer treatment. The most important challenges for the successful clinical use of bacteria are ensuring their preferential tumor colonization and initiating functional tumor-specific immunity. In the current work, we describe the influence of the gut microbiome on Escherichia coli Nissle 1917 (EcN) strain-mediated cancer therapy in a mouse tumor model. Here we demonstrate that gut microbiome modulation can be beneficial for colonization of EcN in tumor tissues and lead to improved survival of tumor-bearing mice treated with EcN. ABSTRACT: In the past, different bacterial species have been tested for cancer therapy in preclinical and clinical studies. The success of bacterial cancer therapy is mainly dependent on the ability of the utilized bacteria to overcome the host immune defense system to colonize the tumors and to initiate tumor-specific immunity. In recent years, several groups have demonstrated that the gut microbiome plays an important role of modulation of the host immune response and has an impact on therapeutic responses in murine models and in cohorts of human cancer patients. Here we analyzed the impact of the gut microbiome on tumor colonization and tumor therapy by the Escherichia coli Nissle 1917 (EcN) strain. This EcN strain is a promising cancer therapy candidate with probiotic properties. In our study, we observed significantly better tumor colonization by EcN after antibiotic-induced temporal depletion of the gut microbiome and after two intranasal applications of the EcN derivate (EcN/pMUT-gfp Kn(r)) in 4T1 tumor-bearing syngeneic BALB/c mice. In addition, we demonstrated significant reduction in tumor growth and extended survival of the EcN-treated mice in contrast to phosphate-buffered saline (PBS)-treated tumor-bearing control animals. Multispectral imaging of immune cells revealed that depletion of the gut microbiome led to significantly lower infiltration of cytotoxic and helper T cells (CD4 and CD8 cells) in PBS tumors of mice pretreated with antibiotics in comparison with antibiotic untreated PBS—or EcN treated mice. These findings may help in the future advancement of cancer treatment strategies using E. coli Nissle 1917.