Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1β

Abstract

Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (ΔppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after ΔppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1β and TNF-α were markedly increased in tumors colonized by ΔppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1β and TNF-α returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1β and TNF-α. We found that macrophages and dendritic cells were the main producers of TNF-α and IL-1β. Inhibiting IL-1β production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1β or TNF-α in conjunction with Salmonella therapy. These findings suggested that IL-1β and TNF-α play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy.

Activation of inflammasome by attenuated Salmonella typhimurium in bacteria‐mediated cancer therapy

“…TNF‐α induced tumoricidal effects associated with Gram‐negative tumor‐colonizing bacteria, but there is no explanation for the contrary antitumor effect between ΔppGpp Salmonella and MG1655. Our recent publication indicated that attenuated ΔppGpp Salmonella triggered effective IL‐1β/TNF‐α‐mediated immune responses in the tumor, leading to significant tumor suppression in the early stage of bacterial therapy . This study was the first to show that IL‐1β plays a critical role in Salmonella ‐mediated cancer therapy.…”

Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy

“…Although KST0650 was highly attenuated, it preferentially accumulated in tumor cells in vivo, which was almost comparable with the levels of other well-known cancer targeting strains, such as VNP20009, SL∆ppGpp (∆relA∆spoT), and A1-R 13,18,45 . Despite it could effectively target, colonize, invade tumors, and reduce tumor growth rate slightly as compared with PBS only, which helps prolong mice survival, its tumor-curing effect was not observed obviously in a tumor-bearing mouse model, suggesting that KST0650 monotherapy does not show anti-tumor effect effectively.…”

“…This strain selectively targeted the tumor in vivo with tumor: liver ratios of 2,000:1, and Salmonella colonization was not detected in normal tissue 2 weeks post-injection 16,17 . Avirulent SL∆ppGpp (∆relA∆spoT) exerted tumor inhibitory effect by recruiting immune cells and inflammatory cytokines 18 . Although certain strains have been attenuated to non-pathogenic levels, their therapeutic activity was modest and transient in the absence of additional manipulation 19 .…”

Antimelanoma Effect of Salmonella Typhimurium Integration Host Factor Mutant in Murine Model

“…This implies that immunological system induction is an essential mechanism of S. enterica antitumor activity [14,56]. In addition, it has been demonstrated that Salmonella-induced cell death of tumor cells is mediated by a mechanism involving apoptosis and autophagy through modulation of the caspase and AKT/mTOR pathways, respectively [11].…”