Merkel cell carcinoma of the skin is often invisible for the body’s immune defense because it silences specific genes of the immune system. Scientists from the German Cancer Consortium (DKTK) at the Medical Faculty of Duisburg Essen University at Essen University Hospital have found a way how to make the tumor a target for the immune system again. Thus, immunotherapeutic approaches in the treatment of skin cancer might become much more effective. In the German Cancer Consortium (DKTK), the German Cancer Research Center (DKFZ) in Heidelberg joins up as a core center in long–term collaborations with partner university institutes and hospitals all over Germany that are specialized in research and treatment with a focus on oncology.

In the present study, scientists from the German Caner Consortium (DKTK) at Essen University Hospital have been the first to discover the mechanisms that the cancer cells use for their camouflage. The tumor uses so–called epigenetic mechanisms in order to silence genes that are essential for antigen presentation.

“The majority of Merkel cell carcinomas in Europe are caused by infection with the Merkel cell polyoma virus, which strongly manipulates the epigenetics of tumor cells,” said Professor Jürgen Becker, who is last author of the study and head of the DKTK working group “Translational Skin Cancer Research” at Essen University Hospital. “An important chemical label, the histone acetylation, is removed in the reprogrammed cancer cells. This leads to the silencing of various immune genes – a phenomenon that is also known as ‘epigenetic silencing’”. Genes that are involved in the presentation of tumor antigens on the surface of cancer cells are thus being silenced, and the immune system no longer recognizes the tumor cells.

In collaboration with colleagues from the University of Washington and Massachusetts General Hospital in Boston, the scientists have now found two methods to reverse this mechanism. One is to equip the cancer cells with the missing processed antigens. The cancer cells subsequently present them on their surface and are attacked and destroyed by T cells. In further experiments, the researchers blocked the key enzyme that is responsible for the inactivation, histone deacetylase (HDAC). As a result, the genes that are responsible for antigen presentation were reactivated and the tumor cell surfaces were loaded with more HLA again.

“Our results show that the camouflage in Merkel cell carcinoma can be reversed pharmacologically,” said Becker, a physician. He is confident that the new findings will improve clinical outcomes of immunotherapies to treat this type of skin cancer. “First we will test the effectiveness of various combination therapies with clinically applicable HDAC inhibitors. The next goal is to conduct clinical trials with patients for whom immunotherapeutic approaches have been ineffective until now.”

The article, "Epigenetic priming restores the HLA class–I antigen processing machinery expression in Merkel cell carcinoma," was published in the journal Scientific Reports.