AsianScientist (Feb. 9, 2017) – Researchers have enhanced the cancer-killing effect of Salmonella bacteria by making it express the protein of another bacteria. Importantly, the results published in Science Translational Medicine also showed that the modified bacteria did not cause toxicity in mice.
Although bacteria are normally thought of as harmful in the context of infections, scientists have been investigating the use of bacteria to kill cancer cells. This approach takes advantage of the fact that cancerous tissue usually have abnormal blood vessels, giving rise to low oxygen conditions favored by anaerobic bacteria.
“These tumor microenvironments are suited to colonization by, and facilitate proliferation of, such bacteria,” explained study corresponding author Professor Min Jung-Joon from Chonam National University Medical School.
“Once bacteria colonize and proliferate in cancer tissue, they activate anticancer immunity, leading to tumor regression.”
The catch, however, is the strain of bacteria used must tread the fine line between killing the tumor and harming the host. To get around this problem, Min and his team used a weakened strain of Salmonella typhimurium but enhanced its immune-activating capabilities by engineering it to express a flagellum protein (FlaB) from a different strain, Vibrio vulnificus.
In previous work, the researchers had developed a strain of S. typhimurium that lacked the ability to produce a key metabolite and was consequently much weaker. When injected into mice, this weakened strain initially colonized the liver and spleen, but because they could not survive once phagocytosed by macrophages, were found in 10,000-fold higher numbers in tumor tissue by three to four days after injection.
“FlaB-secreting Salmonella targeted to the tumor microenvironment then exerted enhanced tumor-suppressive effects through two-step activation of TLR4 and TLR5 signaling pathways. First, bacterial growth in the tumors increased infiltration and activation of immune cells, which appeared to be mediated through TLR4 signaling,” Min told Asian Scientist Magazine.
“Secondly, the recruited immune cells were likely further activated by the TLR5 signaling triggered by in situ–secretion of FlaB in the same microenvironment. These activated effector cells should be able to kill tumor cells by producing cytotoxic mediators including reactive oxygen species, nitric oxide, proteases, membrane-perforating agents and cytokines.”
The FlaB-secreting Salmonella were able to suppress both the growth and metastasis of tumors in mice, presumably through the cooperative activation of the TLR4 and TLR5 pathways. In fact, the treatment was almost too successful, leaving the tumor tissues so severely damaged that it was difficult for the investigators to analyze the immune response.
“Our next step is to engineer smart bacteria that they can conditionally express payload in tumor-specific manner without any deliberate intervention for gene expression. For that, we currently are developing quorum sensing and environmental sensing systems for gene expression,” Min said.
The article can be found at: Long et al. (2017) Two-step Enhanced Cancer Immunotherapy with Engineered Salmonella typhimurium Secreting Heterologous Flagellin.
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