In recent years, combined chemo- and immunotherapies have significantly contributed to improving the chances of survival for lymphoma patients. However, physicians are not yet able to assist patients with rapidly recurring lymphomas that are unaffected by therapy (tumors in the lymphatic system, such as in lymph nodes or the spleen). An MDC research group headed by Dr. Armin Rehm and Dr. Uta E. Höpken has now found the mechanism that is responsible for this phenomenon and that could possibly be used to inhibit tumor growth in the future.
Interaction of immune and lymphoma cells
In tumors of the spleen and lymph nodes, the interaction between cancer and the immune system is even more perfidious than in solid tumors such as colon or prostate cancer. As the team led by Armin Rehm and Uta E. Höpken has shown, existing blood and immune cells are reprogrammed in their maturation and functional states in such a way that they not only promote lymphoma tumor growth, but also protect the tumor from attacks by the immune system. The researchers also found that special immune cells, the dendritic cells (DCs), play a key role in this process.
Since lymphoma cells usually do not grow outside the body, the researchers pondered what effect the immediate environment has on the survival and cell division of these tumor cells. Observations conducted in the clinic had already shown the interdependence of aggressive lymph gland cancer cells and their surrounding microenvironment. But why exactly do lymphoid defense mechanisms fail so blatantly? To answer this question, the team first identified which immune cells in the lymph node and spleen interact with the lymphoma cells.
The role of DCs and the C/EBPβ gene
In experiments conducted with mice, the Berlin researchers were able to show that the tumors of an aggressive lymphoma grew much slower after they had systematically deactivated the dendritic cells. In addition, they discovered that dendritic cells that are isolated from lymphoma-bearing lymphoid organs have a lower maturation state than usual. Furthermore, these cells release growth factors that promote lymphoma growth and are significantly inferior in their ability to stimulate protective T lymphocytes (white blood cells) and thus activate normal defense functions.
A specific gene is responsible for these changes, the transcription factor C/EBPβ. When dendritic cells come into contact with lymphoma cells, they upregulate the activity of this gene. As a result, the DCs remain in an immature state. In addition, the gene ensures the release of tumor-promoting, inflammatory factors. By depleting C/EBPβ in the mouse model, the immunocompetence of the dendritic cells once again improves. And as a result they no longer promote lymphoma growth.
The researchers are now working on developing drugs that inhibit C/EBPβ expression or force the maturation of dendritic cells. In this way, they hope to strengthen the immune system and deactivate processes that promote cancer growth. The team has already tested the pharmacological inhibitor rapamycin and found that it significantly reduces the growth-promoting function of DCs. This success provides good reason to search for further targeted inhibitors of C/EBPβ expression.
Funding medical research: Wilhelm Sander Foundation
This research project received €340,000 Euro in support from the Wilhelm Sander Foundation. The purpose of the foundation is to promote medical research, particularly projects contributing to the fight against cancer. Since the foundation was established, it has granted more than €220 million in research funding in Germany and Switzerland. This makes the Wilhelm Sander Foundation one of the most important private research foundations in the German-speaking world. It was endowed by the estate of the Bavarian entrepreneur Wilhelm Sander, who died in 1973.
Key publications from this project
Rehm A*, Gätjen M, Gerlach K, Scholz F, Mensen A, Gloger M, Heinig K, Lamprecht B, Mathas S, Begay V, Leutz A, Lipp M, Dörken B, Höpken UE* (2014). Dendritic cell-mediated survival signals in Em-Myc B cell lymphoma depend on the transcription factor C/EBPb. Nature Communication 5: 5057-5070; IF: 10.1
Gätjen M, Brand F, Grau M, Gerlach K, Kettritz R, Westermann J, Anagnostopoulos I, Lenz P, Lenz G, Höpken UE*, Rehm A* (2016). Splenic marginal zone granulocytes acquire an accentuated neutrophil B-cell helper phenotype in chronic lymphocytic leukemia. Cancer Res. 15: 5253; IF: 8.6