Searching Salmonella infections for a cancer cure

Picture source: Science News

The cure for cancer has been used as a talking point for decades. Even the current US president, Joe Biden, promised to cure cancer during his campaign. We certainly don’t need to convince anyone that studying anticancer therapies is an important research topic.  According to the CDC, in the United States alone, there are 1.7 million people diagnosed with cancer and $185 billion USD are spent on cancer care each year. There is a lot of available funding for cancer research and many different avenues are being explored.

Researchers are starting to explore if anti-cancer therapies can be found in other diseases. One such example was a research in Uruguay, where Mónaco and collegues used Salmonella infection to target melanoma cells. Melanoma happens when the melanin-producing skin cells turn cancerous. It is one of the most lethal forms of skin cancer with rising prevalence. Unfortunately, surgical removal is only effective during early stages of this cancer and therapies to treat later stages are yet to be established.

The study by Mónaco and colleagues joins others looking into the anticancer activity of bacteria, specifically those that survive in anaerobic conditions. Salmonella survives in both aerobic and anaerobic conditions meaning they could target both small toxic tumors and large hypoxic tumors. They also replicate intracellularly – even inside tumors.

Salmonella can survive and replicate inside macrophages and can be spread to other areas of the body through the circulation of these cells. This is a concern for Salmonella infections, but could this be an advantage when targeting tumors? Let’s see what happens when Salmonella infects a cell.

Salmonella infection can lead to the assembly and activation of the inflammasome. The inflammasome is a complex of multiple proteins that activates inflammatory responses to infection. NLRP3 is a special type of inflammasome that recognizes either flagellin and LPS or signals related to infection-related cell damage. This leads to the secretion of cytokines like  IL-1β or IL-18 and then to pyroptosis, an inflammatory cell death. A pyroptosis-related protein that forms pores, Gasdermin D (GSDM-D),can have an anti-tumor effect.

Now that we know all the characters in this story, we can begin to uncover how Salmonella infection contributes to antitumor effects according to Mónaco et al.:

1) Salmonella-infected tumor cells show signs of pyroptosis including expression of GSDM-D.

2) The transcript of caspase-11 was induced in Salmonella infected tumor cells in vitro while caspase 1 protein was activated. This indicated inflammasome activation in vitro.

3) In melanoma-bearing mice, Salmonella infection led to increased expression of IL-1β and inflammasome-related genes Nlrp3 and Nlrc4 in the immune cells within the tumors. This may lead to tumor growth suppression as shown by previous research. Interestingly, detection of inflammasome-related genes decreased over time. Can Salmonella-based therapy only have a transient effect?

4) Flagellin is a protein in gram-negative bacteria (like Salmonella) that makes up a hairlike structure allowing bacteria to swim. The presence of flagellin can activate caspase-1, which then activates the NLRC4 inflammasome rather than the NLRP3. When flagellin was removed from Salmonella, theinfection still had an anti-tumor effect. This tells us that the NLRP3 inflammasome, not the NLRC4, is the main player in tumor supression.

5) M1 macrophages are required for the anti-tumor effects of Salmonella infection. During infection, Salmonella recruits high quantity of M1 macrophages to the site of the tumor where CASP-1 and other molecules associated with the pro-inflammatory phenotype of macrophages are activated leading to a proinflammatory anti-tumor phenotype. In fact, macrophage depleted melanoma-bearing mice completely lost its antitumor responses by Salmonella.

Although we apprehend that Salmonella infection can help target tumors through the activation of the immune system, more studies are needed to better understand this effect. I am particularly interested to see some combination studies utilizing Salmonella infection and currently employed anticancer therapies. These creative approaches to cancer treatments give us hope that more options will soon be available.

Source:

Mónaco A, Chilibroste S, Yim L, Chabalgoity JA, Moreno M. Inflammasome activation, NLRP3 engagement and macrophage recruitment to tumor microenvironment are all required for Salmonella antitumor effect. Cancer Immunol Immunother. 2022 Sep;71(9):2141-2150. doi: 10.1007/s00262-022-03148-x.

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