Inhibiting cutaneous T-cell lymphoma by fighting bacteria

Disease and treatment 6. feb 2022 3 min Professor Niels Ødum, MD Lise Maria Lindahl Written by Morten Busch

Cancer and bacteria are seldom considered to be two sides of the same coin, but this applies to a serious type of skin cancer called cutaneous T-cell lymphoma. The bacteria do not cause the disease but intensify it. Now, researchers have succeeded in inhibiting cutaneous T-cell lymphoma by combatting Staphylococcus aureus in the skin. Although the bacteria eventually returned, the experiments have provided hope of finding methods to inhibit both the bacteria and lymphoma in the long term.

Staphylococcus aureus is everywhere, coexisting with all the other bacteria on mucous membranes internally and externally – for example in the nose, mouth and skin of almost one in three people. For decades, however, this specific bacterium has also been suspected of playing a key role in a rare but deadly form of skin cancer called cutaneous T-cell lymphoma. This was supported by the discovery that the skin of most people with severe cutaneous T-cell lymphoma is colonised by enterotoxin-producing Staphylococcus aureus. Now a group of researchers has investigated what happens if you eliminate them.

“Intravenous treatment for 10 days with antibiotics and subsequent oral treatment for 14 days enabled us not only to eradicate the bacteria and inhibit the symptoms of cutaneous T-cell lymphoma but also to reduce the proportion of malignant T cells in skin lesions. Unfortunately, the bacteria reappeared after treatment ended, but we are now investigating substances that can eliminate the bacteria without creating resistance so that we can permanently inhibit the lymphoma and improve the quality of life of these people,” explains Lise Lindahl, a doctor at the Department of Clinical Medicine and Department of Dermatology and Venereology, Aarhus University and Aarhus University Hospital.

Accelerating lymphoma

Cutaneous T-cell lymphoma is a rare type of lymphoma and a subgroup of non-Hodgkin’s lymphoma. For the vast majority, non-Hodgkin’s lymphoma adversely affects the immune system’s memory, B cells. Conversely, cutaneous T-cell lymphoma adversely affects the T cells, which find and kill cells infected by either a virus or a bacterium.

“Whether staphylococci play a role in cutaneous T-cell lymphoma or result from it has been long debated. Staphylococci increase the severity of another skin disease, atopic dermatitis, and staphylococci secrete enterotoxins. Two recent studies showed that enterotoxins – at least in the laboratory – seemed to be able to make the malignant T cells divide faster and thus become more malignant. So the bacteria seem to be accelerating the lymphoma,” says Niels Ødum, Professor, LEO Foundation Skin Immunology Research Center, University of Copenhagen, who is leading the project together with professor Lars Iversen from Aarhus University.

The researchers therefore decided to investigate what happens to eight people with cutaneous T-cell lymphoma if they used antibiotics to eliminate the bacteria. The skin of all eight was severely affected by tumours and/or skin redness. Ten days of intravenous and 14 days of oral treatment with broad-spectrum antibiotics provided marked improvement.

“The 10-day course of antibiotics not only eradicated the staphylococci from the lesions in their skin but also reduced the proportion of malignant T cells in the skin and the clinical symptoms of cutaneous T-cell lymphoma, inhibiting both the bacteria and the lymphoma. The tumours decreased in size, and the characteristic skin redness became noticeably less,” explains Lise Lindahl.

Other ways to combat staphylococci

Unfortunately, the staphylococci reappeared after antibiotic treatment ended for most of the eight – and in fact the same clone and thus also the same enterotoxins. Since many people naturally have Staphylococcus aureus and they are ubiquitous, the bacteria returning was not surprising. Treatment with antibiotics is not a long-term solution either.

“Aggressive antibiotic treatment is relevant for people with clinically severe and life-threatening Staphylococcus aureus infections, but such lifelong treatment to prevent skin colonisation is neither feasible nor recommended because it risks side-effects and antimicrobial resistance. Instead, we are focusing on finding other ways to prevent staphylococci from erupting during this lymphoma,” says Lise Lindahl.

This strategy has two aspects. One is trying to hinder the staphylococci by finding substances that improve the skin barrier. The tumour cells overexpress various signalling molecules called cytokines that destroy the skin, which impairs wound healing, preventing a functional skin layer from forming.

“Skin that is exposed to cytokines provides ideal growth conditions for the staphylococci, and since they also help to drive the lymphoma, they are mutually reinforcing. If patients are treated with novel drugs that block the secretion of cytokines by cancer cells or their effect on skin cells, the skin will become more resistant to bacterial colonisation, which would solve half the problem,” emphasises Niels Ødum.

However, the researchers are not just testing this hypothesis to solve the first part of the challenge. The other element of the strategy being pursued intensely is to try to discover substances that can kill the bacteria that continue to recolonise lesional skin.

“Until someone finds a cure for cutaneous T-cell lymphoma itself, we must find alternatives to antibiotics that are suitable for permanent use – such as drugs that do not create resistance and have no side-effects. Here, too, we are engaged in some very promising trials that have aroused great interest among companies, and we hope within a few years to be able to complete these studies and then offer a treatment that will not only prolong these people’s lives but also significantly improve their quality of life,” explains Niels Ødum.

“After decades of suspecting that bacteria can aggravate cutaneous T-cell lymphoma, the role of staphylococci has now been proven. This has given us completely new weapons to combat this type of cancer, and it demonstrates the strength of long-term and strong collaboration between universities and hospitals,” conclude the leaders of the project, Niels Ødum.

Staphylococcus aureus and antibiotics in cutaneous T-cell lymphoma” has been published in Dermatology. “Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma” has been published in Blood. In 2015, the Novo Nordisk Foundation awarded a grant to Niels Ødum for the project Staphylococcal Toxins Fuel Cutaneous T-cell Lymphoma and are Novel Targets for Therapy. In 2021, The Novo Nordisk Foundation awarded a Tandem Programme grant to Niels Ødum and Lars Iversen for the project Staphylococcus aureus and Skin Barrier Defects are Novel Therapeutic Targets in Cutaneous T-cell Lymphoma.

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