Heidelberg – Epigenetically active drugs enable areas of the cell’s genetic material to be read that were previously blocked and inaccessible. This leads to the formation of new mRNA transcripts and also new proteins, as scientists from the German Cancer Research Center and the University Hospital of Tübingen have now published. These “therapy-induced epitopes” could help the immune system recognize cancer cells.
Immunotherapies are an integral part of the treatment spectrum for many types of cancer. But not all patients benefit from it. One of the reasons this form of treatment fails may be that the patient’s immune system does not recognize the cancer cells as such. A fundamental prerequisite for the success of these therapies is that cancer cells have protein structures, so-called antigens, on their surface, which the T cells of the immune system can use to distinguish them from healthy body cells.
Such antigens can be cancer-associated proteins (“tumor-associated antigens”) or proteins modified by mutations. But they can also be completely new gene products that arise in tumor cells because completely new areas of genes are read.
Scientists led by Christoph Plass, DKFZ, and Juliane Walz, University and University Hospital of Tübingen, now had the idea of making cancer cells even more visible to the immune system: They equip the cells with completely new antigens – with the help of epigenetically acting cancer drugs.
These active ingredients are prescribed for many types of cancer. They act on the so-called epigenetic marks on the DNA or on DNA packaging proteins, the histones. Epigenetic markings determine whether the cell can read certain areas of the genome in mRNA or not.
These active ingredients include demethylating drugs such as decitabine or the so-called HDAC inhibitors*. They mean that previously blocked, inaccessible areas of the genetic material can be read and new mRNA transcripts are created in the cell.
Treatment of a lung cancer cell line in a culture dish with decitabine and HDAC inhibitors actually induced several thousand new transcripts, as Plass’s team found through RNA analyses. The majority of these new transcripts originated from endogenous retroviruses. These sequences, which make up up to eight percent of the human genome, are considered relics of retroviral infections from times long past. Normally their transcription is blocked by epigenetic mechanisms. The effect of the neoepitopes induced by decitabine and the HDAC inhibitors is much stronger in cancer cells than in healthy cells. Experts see the reason for this difference in the high proliferation rate of cancer cells.
The exciting question now was whether these “therapy-induced transcripts” actually code for immunogenic protein sections, so-called peptides. Juliane Walz’s team tested this using mass spectrometry. The researchers were able to identify 45 “neoepitopes” that appeared on the surface of the skin after treatment Cancer cells were presented. The researchers were able to achieve comparable results with a wide range of different cancer cell lines. Cytotoxic T cells in the culture dish could be activated with the therapy-induced neoepitopes.
Decitabine is often used, among other things, to treat acute myeloid leukemia (AML). The researchers also discovered therapy-induced neoepitopes in the blood of AML patients receiving decitabine therapy – an important indication that this phenomenon is not an artifact from the culture dish.
“The induction of neoantigens by epigenetic agents could be a new way to use drug combinations to increase the effectiveness of cancer immunotherapies. With further investigations, we want to find out whether it is possible to develop targeted immunotherapies against these neoantigens,” says study leader Christoph Plass.
Goyal A, Bauer J, Hey J et al.: DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
Nature Commmunications 2023,
* HDAC inhibitors = histone deacetylase inhibitors
With more than 3,000 employees, the German Cancer Research Center (DKFZ) is the largest biomedical research institution in Germany. At the DKFZ, scientists research how cancer develops, record cancer risk factors and look for new strategies that prevent people from developing cancer. They are developing new methods with which tumors can be diagnosed more precisely and cancer patients can be treated more successfully. At the DKFZ Cancer Information Service (KID), those affected, interested parties and specialist groups can receive individual answers to all questions about cancer.
In order to transfer promising approaches from cancer research to the clinic and thus improve the chances of patients, the DKFZ operates translation centers together with excellent university hospitals and research institutions throughout Germany:
National Center for Tumor Diseases (NCT, 6 locations) German Consortium for Translational Cancer Research (DKTK, 8 locations) Hopp Children’s Tumor Center (KiTZ) Heidelberg Helmholtz Institute for Translational Oncology (HI-TRON) Mainz – a Helmholtz Institute of the DKFZ DKFZ-Hector Cancer Institute at the University Medical Center Mannheim National Cancer Prevention Center (together with the German Cancer Aid)
The DKFZ is financed 90 percent by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg and is a member of the Helmholtz Association of German Research Centers.