Staphylococcus bacteria enterotoxins induce resistance in cancer cells

Therapy Breakthroughs 6. feb 2024 4 min Professor Niels Ødum Written by Morten Busch

Researchers involved in combatting cancer are constantly discovering new frontlines. A new discovery shows that the ubiquitous Staphylococcus bacteria can transform lymphoma cells into invulnerable drug-resistant opponents. The new study provides unique insight into how external factors, including bacteria, can affect treatment for cancer.

Anticancer treatment is often described as combatting cancer and its many complications. Now a new groundbreaking study spotlights another aspect for people with cancer and their caregivers. Although people with cutaneous T-cell lymphoma (CTCL) – a type of skin cancer that changes T cells – are known to be especially vulnerable to skin infections, S. aureus now appears to not only actively promote CTCL but helps it to become drug resistant.

“The S. aureus enterotoxins activate the cancer cells so they can resist anticancer drugs. Inhibiting the bacteria or their enterotoxins can remove this resistance, enabling new treatment options for cancer. The revelation that ordinary bacteria can induce cancer cells to become drug resistant sheds new light on how external factors such as enterotoxins influence treatment. It also emphasises the importance of treating people with cancer for bacterial infections,” explains a main author, Niels Ødum, Professor, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Denmark.

Sézary syndrome and T cells

Sézary syndrome is a rare but serious type of CTCL. T cells normally help to combat infections and maintain the balance of the immune system. In CTCL, the T cells have transformed into cancer T cells.

“The cancer T cells grow and divide uncontrollably. This leads to various skin symptoms, redness, itching and scaly patches, which can affect most of the body. Even worse, the T cells disrupt the normal immune response in the skin, making it more vulnerable to bacterial infections and other conditions,” says Niels Ødum.

People with Sézary syndrome frequently have S. aureus present. Infections can worsen their condition and reduce the effectiveness of anticancer treatment. Many with severe Sézary syndrome may eventually die from the infections themselves because their immune system no longer functions.

“Researchers have previously wondered whether the infections exacerbate the cancer. Antibiotics benefit people with Sézary syndrome, indicating that the bacterial infections influence the activity of the cancer cells. Nevertheless, we did not know whether this effect was direct or indirect,” notes Niels Ødum.

Tipping the balance to favour the cancer cells

Many unanswered questions remained before the researchers could determine whether S. aureus could influence the development of cancer and the possible mechanisms.

“We had various pieces of the puzzle. For example, I happened to be working on how S. aureus enterotoxins affect T cells, and this proved useful,” explains Niels Ødum, adding:

“I started to see a pattern and thought: could these enterotoxins possibly overwhelm the system because they destroy the normal interaction between the healthy cells and the cancer cells – thereby tipping the balance to favour the cancer cells? This was no longer a wild thought but an incredibly logical idea.”

The researchers’ idea was simple but still speculative. Could the S. aureus, which can cause infections, also activate the cancer cells to become resistant to anticancer drugs? They tested their hypothesis by examining blood samples from 17 people with Sézary syndrome.

“As Sézary syndrome develops, the malignant clones are found in high numbers in the bloodstream and lymphatic system” explains Niels Ødum.

Destroying the cancer cells’ shield

The researchers isolated immune cells from the blood, thereby also capturing and examining some of the skin cancer cells. They performed laboratory experiments to determine the characteristics of the cancer cells, the development of the disease and how the cells respond to treatment.

“We exposed the cells to romidepsin, a histone deacetylase inhibitor used to treat people with various types of skin cancer, including CTCL. Some cells were exposed to S. aureus enterotoxins and some were not,” says Niels Ødum.

To determine whether the bacteria themselves or the substances they secreted caused any effects, the researchers exposed the cancer cells to the liquid surrounding S. aureus. They thus hoped to reveal whether the interaction between cancer cells and S. aureus actually occurred through the enterotoxins in the liquid.

“Our experiments showed that secreted enterotoxins enable the cancer cells to develop a shield that makes them resistant to the anticancer treatment. We have similarly found that inhibiting S. aureus or their toxins inhibits the cancer cells’ resistance. In other words, killing the S. aureus destroys the cancer cells’ shield so they are no longer invulnerable and die from the anticancer therapy,” explains Niels Ødum.

New knowledge

The discovery that the enterotoxins secreted by S. aureus make the difference may prove decisive for understanding the interaction between cancer and bacteria. The researchers were not certain whether the enterotoxins or the residue of dead bacteria most strongly influenced the cancer cells.

“We could not be certain in advance, but now we know that removing the enterotoxins inhibits the effect. And we also found that the S. aureus that do not produce enterotoxins do not have this effect. Since only living bacteria secrete the effective enterotoxins, the effect disappears when the S. aureus are eliminated,” says Niels Ødum.

What distinguishes the new findings from previous ones is the surprising discovery that S. aureus enterotoxins directly change how the cancer cells respond to treatment.

“The S. aureus enable the cancer cells to cope better because they are less strongly affected by medicine. This is a revelation in understanding how cancer cells can develop resistance – not only through genetic mutations in the cancer cell itself but also through the influence of microorganisms. This is the novel aspect,” notes Niels Ødum.

New opportunities for combatting cancer

The new study is useful because this shows how bacteria such as S. aureus can make cancer cells invulnerable to anticancer drugs.

“This is a sequence of events – a vicious circle. We have previously shown that cancer cells can change the skin and destroy the skin barrier so that it cannot protect against bacteria. We also knew that antibiotics resulted in fewer cancer cells in the skin. But we did not know why. The new discovery can probably explain why these bacteria can exacerbate cancer,” says Niels Ødum.

This enables a new way of examining how external factors such as bacterial toxins can influence anticancer treatment.

“This provides new opportunities for combatting CTCL and potentially other types of cancer in which bacteria play a similar role and can strongly influence the effectiveness of treatment. This insight produces new considerations about treatment strategies that focus on targeting the cancer cells but also the bacteria that protect and strengthen them,” explains Niels Ødum.

The results therefore emphasise the need to find ways to combat cancer cells among people with CTCL but also eradicating S. aureus and preventing the skin from being colonised.

“In addition, people with advanced CTCL have often received several types of antibiotics and risk being colonised by multidrug-resistant S. aureus. The good news is that new antimicrobial endolysins, which mimic bacteriophages, can block this effect. Since these new antibiotic-free agents kill both common and multidrug-resistant S. aureus, we are very hopeful that they can be a solution,” concludes Niels Ødum.

Staphylococcus aureus induce drug resistance in cancer T cells in Sézary syndrome” has been published in Blood. In 2021, the Novo Nordisk Foundation awarded a Tandem Programme grant to Niels Ødum and co-author Lars Iversen for the project Staphylococcus aureus and Skin Barrier Defects are Novel Therapeutic Targets in Cutaneous T-cell Lymphoma.

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