Potential pivot for a more effective cancer immunotherapy

The focus is on the messenger substance interleukin-33 (IL-33). If the production of IL-33 in regulatory T cells in the tumor and in the immediate vicinity of the tumor is inhibited, tumor growth is reduced and immunotherapies show increased effectiveness in experimental models. The understanding of this mechanism could contribute to the development of new immunotherapeutic approaches. The results of the study were published in the journal “Nature Immunology” (www.nature.com, DOI 10.1038/s41590-019-0555-2).

Despite impressive clinical success, immunotherapies to combat cancer are ineffective with many patients. Regulatory T-cells, so-called Tregs, which inhibit an immune response directed against the tumor, play an important role here. Scientists of the Biomedical Research Foundation of the Academy of Athens, the Institute of Clinical Chemistry and Laboratory Medicine of the Carl Gustav Carus University Hospital Dresden and the National Center for Tumor Diseases (NCT/UCC) have now been able to show that a special messenger substance – interleukin-33 – found in the Tregs is an adjustable pivot for the function of the cells and for improved effectiveness of immunotherapies in the future.

Regulatory T cells accumulate to a high degree in and around the tumor. They serve an anti-inflammatory function by calming the immune system. However, this supposedly positive response to prevent excessive immune reactions is counterproductive in the tumor and its immediate environment: here, the immune system should be highly active to fight the tumor. Excessive Tregs promote tumor growth and, in many cases, impede the effectiveness of tumor immunotherapy.

In contrast to Tregs in other body regions, regulatory T cells in the tumor and its immediate environment have a particularly high content of the messenger substance interleukin-33 (IL-33). As the researchers have now been able to show on the basis of different experimental models, blocking the production of IL-33 reduces the inhibitory properties of the Tregs and thus leads to a decrease in tumor growth and a better effectiveness of immunotherapies. Important for the altered function of the Tregs associated with the absence of IL-33 is likely the increased production of the interferon-gamma protein, which has immunostimulatory properties.

The messenger substance IL-33 could therefore possibly offer a starting point for the targeted attack of the Tregs in the tumor and for changing their functionality. On the other hand, a less targeted attack on all Tregs present in the body could lead to a potentially life-threatening auto-immune reaction. IL-33 is therefore a potential target on which future therapies could focus in order to promote the immune system’s fight against cancer.

Publication
Aikaterini Hatzioannou, Aggelos Banos, Theodore Sakelaropoulos, Constantinos Fedonidis, Maria-Sophia Vidali, Maren Köhne, Kristian Händler, Louis Boon, Ana Henriques, Vasiliki Koliaraki, Panagiotis Georgiadis, Jerome Zoidakis, Aikaterini Termentzi, Marc Beyer, Triantafyllos Chavakis, Dimitrios Boumpas, Aristotelis Tsirigos and Panayotis Verginis: An intrinsic role of IL-33 in Treg cell–mediated tumor immunoevasion
Nature Immunology DOI: 10.1038/s41590-019-0555-2

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NCT/UCC Dresden
Dresden has been the second location of the National Center for Tumor Diseases (NCT) after Heidelberg since 2015. The National Center for Tumor Diseases Partner Site Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center (DKFZ), the Carl Gustav Carus University Hospital Dresden, the Carl Gustav Carus Faculty of Medicine at TU Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).
The NCT has set itself the task of linking research and patient care as closely as possible. This enables cancer patients in Dresden and Heidelberg to be treated according to the latest scientific findings. At the same time, the close proximity of the laboratories to the clinic gives the scientists important impulses for their practice-orientated research. The common goal of both locations is to develop the NCT into an international center of excellence in patient-orientated cancer research. The Dresden Center builds on the structures of the University Cancer Center Dresden (UCC), which was founded in 2003 as one of the first Comprehensive Cancer Centers (CCC) in Germany. Since 2007, the UCC has been funded by the German Cancer Aid (Deutsche Krebshilfe e.V. (DHK) as an “Oncological Center of Excellence”.

German Cancer Research Center (DKFZ)
The German Cancer Research Center (DKFZ) is the largest biomedical research institution in Germany with more than 3,000 employees. More than 1,000 scientists at the DKFZ are investigating how cancer develops, identifying cancer risk factors and looking for new strategies to prevent the development of cancer. They are developing new methods with which tumors can be diagnosed more precisely and cancer patients can be treated more successfully. The staff of the Cancer Information Service (KID) educate patients, relatives and interested citizens about the widespread disease of cancer. In cooperation with the University Hospital in Heidelberg, the DKFZ has established the National Center for Tumor Diseases (NCT) in Heidelberg, where promising findings from cancer research are transferred to the clinic. In the German Cancer Consortium Dresden (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. The combination of excellent university medicine with the top-class research of a Helmholtz Centre is an important contribution to improving the chances of helping cancer patients. The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden- Württemberg. It is a member of the Helmholtz Association of German Research Centers.

Carl Gustav Carus University Hospital Dresden
The Carl Gustav Carus University Hospital Dresden offer medical care at the highest level. As a hospital providing this level of care, it covers the entire spectrum of modern medicine. The University Hospital unites 20 clinics and polyclinics, four institutes and ten interdisciplinary centers that work closely with the clinical and theoretical institutes of the Medical Faculty.
With 1,295 beds and 160 places for the day-care treatment of patients, the University Hospitals Dresden is the largest hospital in the city and, at the same time, the only hospital providing maximum care in Easters Saxony. Around 860 doctors cover the entire spectrum of modern medicine. 1,860 nurses take care of the patients’ wellbeing. Important treatment focuses of the University Hospital include the care of patients suffering from cancer, metabolic and neurodegenerative diseases.
Germany’s largest hospital comparison by the news magazine “Focus” certifies that the Carl Gustav Carus University Hospital Dresden has an excellent quality of treatment. University Medicine Dresden therefore occupies second place in the nationwide ranking.

Carl Gustav Carus Medical Faculty at Technische Universität Dresden
University Medicine Dresden, consisting of the Carl Gustav Carus Faculty of Medicine and the eponymous University Hospital, specialises in research in the areas of oncology, metabolic as well as neurological and psychiatric illnesses. In these areas, the topics of degeneration and regeneration, imaging and technology development, immunology and inflammation, as well as prevention and healthcare research, are of particular interest. International exchange is a prerequisite for top-level research – University Medicine Dresden manifests this idea with employees hailing from 73 nations and numerous cooperations with researchers and teams from all over the world.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR)
The Helmholtz-Zentrum Dresden-Rossendorf (HZDR) conducts research in the fields of energy, health and matter. Central to this research are the following questions:
-how can energy and resources be used efficiently, safely and sustainably?
-how can cancer diseases be better visualised, characterised and effectively treated?
-How do matter and materials behave under the influence of high fields and in the smallest dimensions?
To answer these scientific questions, the HZDR operates large infrastructures, which are also used by external institutions: Ion Beam Centre, High Magnetic Field Laboratory Dresden and ELBE Centre for High-Power Radiation Sources.
The HZDR is a member of the Helmholtz Association, has five locations (Dresden, Freiberg, Grenoble, Leipzig, Schenefeld near Hamburg) and employs almost 1,200 people – around 500 researchers including 170 PhD students.