People with cutaneous T-cell lymphoma experience microscopic skin lesions that cause serious symptoms, reducing their quality of life and opening entry sites for potentially dangerous bacterial infections. Now researchers have solved the mystery of why the skin is compromised and how to avoid this. They now hope that the lives of people with cutaneous T-cell lymphoma can be extended and that combination therapy may be able to completely cure it in the long term.
People with cutaneous T-cell lymphoma experience horrible itching and stinging, and red plaques are also a breeding ground for potentially deadly bacteria in advanced stages of the disease. The pathological processes that compromise the skin barrier have remained unknown, but a new study has solved that part of the mystery of this disease.
“We found that the T cells that have developed into cancer cells secrete certain cytokines – signalling substances – that downregulate the production of a type of protein that is crucial for building the skin barrier. We have also showed that the skin remains intact by blocking this downregulation. This also means that we can hopefully prevent the bacterial colonisation that can ultimately become fatal among people with advanced disease. We can also delay this and, by combining the treatment with other drugs, we hope to cure the disease eventually,” explains Niels Ødum, Professor, LEO Foundation Skin Immunology Research Center, University of Copenhagen.
Water loss and compromised expression
Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. The researchers examined people with mycosis fungoides, which accounts for almost 50% of the cases of lymphoma, and people with the rarer Sézary syndrome. The researchers tried to find the differences between tissue samples from cancerous skin and healthy skin of people with cutaneous T-cell lymphoma.
“The samples came from sites at which the cancer had not yet been established. We could thus see which substances the cancer cells make and which substances they stimulate the adjacent cell environment to make. We hoped that this knowledge could explain why the skin changes shape and stops making the protective layer it normally has. Without this layer, people are much more susceptible to potentially dangerous infections,” says Niels Ødum.
The studies were conducted on artificial skin: three-dimensional models built from real human skin cells. The researchers could thus better measure and control small changes in the skin’s delicate balance.
“In the areas adjacent to the cancerous T cells, more of the cytokines, which are normally used to activate the immune system, were secreted. Unfortunately, the cytokines also cause transepidermal water loss and compromise the expression of the skin barrier proteins filaggrin and filaggrin-2, which normally have a protective effect,” explains Niels Ødum.
The skin barrier and filaggrin help to keep the skin cells tightly together. In healthy, uncompromised skin, bacteria cannot slip through. The new research now provides an important part of the reason why the skin is destroyed and thus creates a breeding ground for serious infection.
“A compromised skin barrier provides ideal growth conditions for bacteria such as staphylococci. Previous research has even shown that the infections did not merely result from cutaneous T-cell lymphoma but also accelerate its development. Staphylococci, for example, secrete a toxin that can cause cancer cells to divide faster and thus become more malignant. So the bacteria and cancer cells seem to reinforce each other’s presence,” says Niels Ødum.
JAK1 inhibitors are a mechanism for counteracting the repression of filaggrins and a clinically approved JAK inhibitor called tofacitinib is already used to treat rheumatic diseases.
“This means we do not need to start from scratch with testing the drug. We expect that we can rapidly offer it to some patients in a trial and then determine whether it actually works in the way we expect or not,” explains Niels Ødum.
Under Niels Ødum’s leadership, the new results have been achieved through a unique collaboration that cuts across several disciplines and institutions, with the participation of researchers from the University of Copenhagen led by PhD student Maria Gluud in close collaboration with Lars Iversen and his team at the Department of Dermatology, Aarhus University Hospital and Maria Rørbæk Kamstrup, a doctor at the Department of Dermatology, Bispebjerg and Frederiksberg Hospital in Copenhagen.
The group is now optimistic about the future treatment of cutaneous T-cell lymphoma.
“We hope we can create a trivalent treatment somewhat like the one for tuberculosis. We are already testing completely new substances that can reduce the number of infections and thus remove the extra fuel they give to cutaneous T-cell lymphoma. With our new results, we can probably remove the skin barrier defects and thus the severe discomfort and increased risk of infection they cause. Finally, we need to find a treatment, and promising trials are also underway. So we are very optimistic about one day being able to completely cure the disease, although there is still a long way to go,” concludes Niels Ødum.