Melanoma cells become invisible to immune system due to inflammation caused by treatment

16 October 2012

A research team led by Bonn University has discovered that an inflammatory reaction caused by the treatment given for a tumour causes the tumour cells to temporarily alter their external characteristics and thus become invisible to the body's defence cells. This knowledge forms an important foundation for the improvement of combination therapies. The results have been published online in the journal Nature.

Melanoma is so dangerous because it tends to metastasize early on. New treatment approaches utilize, among other things, the ability of the immune defence to search out and destroy malignant cells. Yet this strategy is often only temporarily effective.

In Germany, approximately 15,000 people develop melanoma annually and approximately 2,000 people die from it every year. Malignant melanoma is the most frequently fatal skin diseases. The particular malignancy is based on the fact that small tumours can spread via the lymphatic vessels and the bloodstream. For many years, the working group under Prof. Dr Thomas Tüting, Director of the Laboratory for Experimental Dermatology at the Bonn University Hospital, has investigated the effect of a targeted immune therapy with tumour-specific defence cells.

Tumor cells behave like a wolf in sheep’s clothing

In trials on mice that congenitally develop melanoma, the researchers were able to destroy advanced tumours using so-called cytotoxic T-cells. “But they recover after some time — just as they do in patients in the hospital,“ explain Dr. Jennifer Landsberg and Dr. Judith Kohlmeyer, lead authors of the study. This form of therapy triggers inflammation. Now the researchers have discovered that the melanoma cells change their external characteristics precisely via this accompanying inflammatory reaction. “They behave like wolves in sheep’s clothing and thus evade detection and destruction by defence cells,“ says Marcel Renn, also a lead author of the study.

The immune system can fight tumours – but it can also protect them

On the search for the underlying mechanisms, the researchers pointed histological investigations of tumours in the right direction: Therapy-resistant melanomas demonstrated a significantly stronger inflammatory reaction with many scavenger cells of the immune system, the so-called macrophages. A messenger primarily released from these immune cells - the tumour necrosis factor-alpha - was able to bring about the change in character of the melanoma cells directly in the Petri dish in the laboratory. Cells treated in this way were subsequently hardly detected by the defence cells.

“The immune system is like a double-edged sword,“ explains Prof. Tüting. “It can fight the tumour — but it can also protect it.“ Such changes in the tumour tissue are probably of great importance for the formation of resistance to therapy. “According to more recent discoveries, treatment with inhibitors which prevent signal transmission in tumour cells is also affected by this,“ remarks Prof. Tüting.

Melanoma cells lose their typical characteristics

Molecular genetic investigations revealed that melanoma cells from therapy-resistant tumours had lost the characteristics typical for pigment cells. Instead, they demonstrated traits of connective tissue cells. “It is possible that melanoma cells undergo this change in character so easily because they originate from the embryonic development of cells in the neural crest which can also form connective tissue and nerve cells,“ says Prof. Dr. Michael Hölzel, co-author from the Institute for Clinical Pharmacology and Clinical Chemistry at the Bonn University Hospital.

Results can also be transferred to humans

Findings initially gained from laboratory mice were also able to be reproduced by the team of researchers with human melanoma cells and various associated defence cells in the Petri dish. The melanoma cells likewise reacted to the messenger tumour necrosis factor-alpha with a loss of pigment cell characteristics and could then no longer be detected by pigment-cell-specific defence cells.

“Detection by other defence cells which can search out specific genetic changes in the melanoma cells was not affected by this, however,“ stresses Prof. Dr. Thomas Wölfel, director of a working group involved in the study at the Medical Clinic III of the Mainz University Hospital.

Important findings for new treatment strategies

As soon as the tumour necrosis factor alpha no longer had an effect on the human and mouse melanoma cells, however, the cells regained their pigment-cell characteristics. Then they were also able to be detected and fought against by all immune defence cells once more. All of these findings yield important information for new treatment strategies.

Thus in the future, defence cells against antigens of various categories and specificity should be used and at the same time, the inflammation utilized by the tumour cells should be therapeutically inhibited. “Our experimental model system will help us to develop optimally effective combination therapies as rapidly as possible,“ says Prof. Tüting. “However, it will still take several years until the clinical application of strategies of this type.“

Further information

Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation, Nature, DOI: 10.1038/nature11538



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