• References

    Chiodi I et al. (2021). Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells. Oncol Rep 45, 96.

    Copland A et al. (2024). Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. EMBO Mol Med 16, 3057–3088.

    Forbes NS (2013). Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10. 785–794.

    Hope HC et al. (2021). Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation. JCI Insight 6, e137761.

    Martín R et al. (2013). Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. Microb Cell Fact 12, 71.

    McCarthy EF (2006). The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 26, 154–158.

    Munir M et al. (2024). William Coley: The pioneer and the father of immunotherapy. Cureus 16, e69113.

    Sedighi M et al. (2019). Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer Med 8, 3167–3181.

    Siegel RL et al. (2024). Cancer statistics, 2024. CA Cancer J Clin 74, 12–49.

    Song S et al. (2018). The role of bacteria in cancer therapy – enemies in the past, but allies at present. Infect Agent Cancer 13, 9.

    Torres A et al. (2016). Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming. J Leukoc Biol 99, 387–398.

    Toso JF et al. (2002). Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20, 142–152.

Could Salmonella Be Our Unlikely Ally in the Fight against Cancer?

31 January, 2025;
Could Salmonella Be Our Unlikely Ally in the Fight against Cancer?

Cancer is an umbrella term for a variety of diseases in which cells grow and proliferate in an uncontrolled fashion, resulting in the formation of tumors. Despite the profound advances made in cancer research in recent years, there is still a way to go, with an estimated two million new cases of cancer and over 600,000 cancer-related deaths occurring in the U.S. in 2024 (Siegel et al. 2024).

While bacteria have had a bad rap (often for good reason), new research has started to shine a more positive light on some of their functions. For example, commensal bacteria in the gut microbiome can prevent the colonization of more sinister pathogens and break down indigestible compounds in food, providing nutrients that we would otherwise be unable to access (Martín et al. 2013).

But could these complex microorganisms be on our side in the fight against cancer? In this blog, we discuss recent advances in bacterial cancer therapy (BCT).

Friend or Foe?

Although modern research has recently become more interested in the idea of using bacteria in anti-cancer therapies, with the number of publications on the topic increasing significantly over the last few decades, the concept is far from new (Sedighi et al. 2019).

As far back as 1891, a surgeon called William B. Coley hypothesized that stimulating the immune system with bacteria would help the body fight against cancer. Thus, he injected Streptococcus pyogenes into a patient with inoperable cancer and, remarkably, the patient’s tumor disappeared. Coley went on to treat almost a thousand patients with inoperable cancer using bacteria and has since been known as the father of immunotherapy (McCarthy 2006).

Bacteria are particularly well suited to this task due to a number of intrinsic features. For example, many strains, such as Salmonella and Streptococcus, have been shown to preferentially gather in tumor tissue. Their flagella structures and chemotactic receptors allow these secret agents to effectively sense molecular signals and invade the enemy territory (Forbes 2013).

However, you may be thinking that injecting patients with live bacteria doesn’t seem like a great idea. And you wouldn’t be entirely wrong! Coley soon learned of the high risk of his treatments when some patients unfortunately died due to infection. A balance between controlling the infection and enabling the therapeutic benefit needs to be struck. So, Coley began to use heat-inactivated bacteria to minimize the adverse effects and try to achieve this delicate equilibrium (Munir et al. 2024).

Today, the genetic engineering of bacteria allows us to reduce side effects even further while simultaneously enhancing tumor-fighting abilities (Song et al. 2018). For example, bacterial strains can be modified to express cytotoxic proteins (like perforin), cytokines, or apoptosis-inducing agents to increase their killing capacity for cancer cells (Forbes 2013).

The ability to easily manipulate bacteria to suit our needs makes them incredibly useful assassins to have on our side.

Myc Drop

The use of BCT in combination with conventional treatments, such as radiotherapy, surgery, chemotherapy, and immunotherapy, has been proposed as a method to overcome the limitations of monotherapies.

Salmonella enterica serovar Typhimurium (STm) is one of the most studied bacteria for cancer therapy due to its tumor-homing features and ability to adapt to harsh microenvironments. Despite these aspects, BCT has thus far not been as effective as previously hoped (Toso et al. 2002).

Thus, Copland et al. (2024) set out to uncover the mechanisms by which the immune system and bacteria interact during BCT.

To investigate the impact of an attenuated strain of STm on T cell function, the researchers utilized a mouse model of colorectal cancer (CRC) in Tocky-GreatSmart mice, which express a fluorescent protein in response to T cell receptor (TCR) signaling, crossed with Ifng-YFP reporter mice, which detect interferon gamma (IFNg) signaling.

By analyzing the lymph nodes, spleen, and tumor using flow cytometry, the scientists found that STm treatment provoked a strong IFNg response in CD4 and CD8 T cells. However, many T cells did not show any signs of TCR signaling, indicating a decoupling of TCR signaling and IFNg response in reactive T cells induced by STm treatment. Furthermore, these unconventionally activated T cells were unable to sustain activation following STm infection.

But what exactly is causing this STm-induced disruption of T cell activation? To address this question, Copland et al. performed RNAseq analysis on T cells that were cultured with tumor-conditioned media (TCM) from STm-infected or uninfected tumor organoids and activated by anti-CD3 and anti-CD28 stimulation.

Interestingly, the STm-treated group showed significant differences in the expression of genes involved with metabolic reprogramming, namely the suppression of genes associated with glycolysis and oxidative phosphorylation. This suppression could be pinpointed to STm's selective inhibition of c-Myc, a master metabolic controller, in T cells, leading to their dysfunction.  

So, why does all this matter? Well, knowing what is causing this impairment of T cells will help design better therapies that overcome these limitations. To that end, the researchers attempted to reinvigorate the T cells in this model.

The amino acid asparagine is vital for optimal T cell function and has been shown to maintain the expression of c-Myc (Chiodi et al. 2021, Hope et al. 2021). Salmonella is known to express asparaginase, an enzyme that breaks down asparagine (Torres et al. 2016). Interestingly, the researchers found that genetically modifying the Salmonella to lack asparaginase enabled the restoration of the full functionality of the T cells.

However, while this mutant form of STm was still able to provoke a reduction of the tumors, it did so less efficiently than the bacteria that expressed asparaginase.

Overall, this research shows us that befriending bacteria to work alongside us is not a lost cause. While, in this case, reviving the T cells came at the cost of efficient tumor control, more knowledge of how the immune system and bacterial cells interact will hopefully allow us to engineer a novel BCT that can work in combination with conventional cancer therapies to achieve optimal results in the future.

Interested in Studying Cancer?

Bio-Rad offers a comprehensive selection of cancer antibodies and reagents for all of your research needs.

 

References

Chiodi I et al. (2021). Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells. Oncol Rep 45, 96.

Copland A et al. (2024). Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. EMBO Mol Med 16, 3057–3088.

Forbes NS (2013). Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10. 785–794.

Hope HC et al. (2021). Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation. JCI Insight 6, e137761.

Martín R et al. (2013). Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. Microb Cell Fact 12, 71.

McCarthy EF (2006). The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 26, 154–158.

Munir M et al. (2024). William Coley: The pioneer and the father of immunotherapy. Cureus 16, e69113.

Sedighi M et al. (2019). Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer Med 8, 3167–3181.

Siegel RL et al. (2024). Cancer statistics, 2024. CA Cancer J Clin 74, 12–49.

Song S et al. (2018). The role of bacteria in cancer therapy – enemies in the past, but allies at present. Infect Agent Cancer 13, 9.

Torres A et al. (2016). Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming. J Leukoc Biol 99, 387–398.

Toso JF et al. (2002). Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20, 142–152.

 

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