A new study from the Medical Center – University of Freiburg, Germany, shows why certain combined immunotherapies are particularly effective in helping patients with advanced skin cancer. The two immune checkpoint therapies prevent the tumour from switching off the immune cells. Freiburg researchers have now been able to show for the first time that the IL-21 signalling pathway plays a decisive role in this process by activating important immune cells with greater intensity and in a more targeted manner. The study was published on 19 December in the journal Nature Immunology. The findings now open up the possibility of adding this immune activation to other cancer therapies, thereby strengthening cancer treatments.

"Our results are an important step towards improving the success of immunotherapy in malignant melanoma and transferring it to other types of cancer. We were able to show that the activation of the IL-21 signalling pathway is crucial for the success of combination therapy," said Prof. Dr. Dr. Bertram Bengsch, head of the study and senior physician at the Department of Internal Medicine II at the Medical Center – University of Freiburg. "This mechanism contributes significantly to the fact that patients with skin cancer develop a stronger immune response under combination therapy and thus achieve better survival rates," said Bengsch, who is also a member of CIBSS – Centre for Integrative Biological Signalling Studies at the University of Freiburg and the German Consortium for Translational Cancer Research in Freiburg.

Patients' immune systems point researchers in the right direction 

In the study, the immune system of patients with advanced malignant melanoma was examined at the Skin Tumour Centre of the University Medical Centre Freiburg (Head: PD Dr. Frank Meiß). The patients were treated with immune checkpoint inhibitors, either as monotherapy with anti-PD-1 or as double immunotherapy with anti-CTLA-4 and anti-PD-1. The researchers found that anti-CTLA-4 therapy strengthened a signalling pathway in the patients' immune cells that is triggered by the messenger substance IL-21. As a result, exhausted CD8 T cells were reprogrammed to join the fight against the tumour.

Communication between different immune cell types key to success

"What is exciting is that there is an indirect mechanism," says Bengsch. For example, anti-CTLA-4 therapy increases the production of IL-21 by so-called helper T-cells, which can have an effect on CD8 T-cells. If this communication is prevented, there is no therapeutic effect. The researchers demonstrated this in a mouse model in cooperation with the research group of Prof. Dr. Robert Zeiser, Department of Internal Medicine I at the Medical Center – University of Freiburg and member of CIBSS – Cluster of Excellence Centre for Integrative Biological Signalling Studies at the University of Freiburg.

Results offer new hope for skin cancer patients

The results of the study show that the combination therapy not only induces a quantitatively stronger immune response, but also leads to a qualitative change in the immune cells. These cells developed into cytotoxic effector cells, which are able to fight tumour cells more effectively. "For patients receiving double immunotherapy, this probably means a better prognosis and longer survival," says Bengsch.

Outlook for future research

The researchers now plan to investigate the role of the IL-21 pathway in other types of cancer. In the long term, the findings could lead to new combination therapies that make immunotherapy even more effective. Further studies are needed to further elucidate the exact mechanisms and to optimise therapeutic approaches for different types of cancer.

Original Publication

Zhen Zhang, Marlene Langenbach, Sagar Sagar, Viktor Fetsch, Jonas Stritzker, Elizabeth Severa, Ke Meng, Frances Winkler, Nisha Rana, Katharina Zoldan, Ira Godbole, Sabrina Solis, Jeffrey S. Weber, David Rafei-Shamsabadi, Saskia Lehr, Rebecca Diehl, Ana Cecilia Venhoff, Reinhard E. Voll, Nico Buettner, Christoph Neumann-Haefelin, Tobias Boettler, Maike Hofmann, Melanie Boerries, Frank Meiss, Robert Zeiser, Robert Thimme, Ramin S. Herati & Bertram Bengsch (2024): Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells. Nature Immunology: DOI: 10.1038/s41590-024-02027-0

CIBSS Profile of Prof. Dr. Dr. Bertram Bengsch

CIBSS Profile of Prof. Dr. Robert Zeiser

Original Press Release of the Medical Center – University of Freiburg