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MDC and Charité Researchers Identify Dendritic Cell Mechanism Driving Lymphoma Tumor Growth

Instead of supporting the body in its fight against cancer, specialized immune cells called dendritic cells (DCs) may also have just the opposite effect. In cancers of the colon, stomach, breast and prostate, DCs have been shown to contribute to tumor growth and to the shielding of the tumor from the immune defense system. Now the hematologist Dr. Armin Rehm (MDC and Charité – Universitätsmedizin Berlin) and the immunologist Dr. Uta Höpken (MDC) have shown for the first time that this phenomenon also occurs in lymphomas. The researchers have also identified the molecular mechanism that induces the immune cells to promote lymphoma tumor growth. (Nature Communications, doi: 10.1038/ncomms6057).*

The immune cells at issue here are the dendritic cells (DCs), so called because of their tree-branch-like projections. Their task is normally to capture and present antigens derived from microorganisms or tumors to T cells, which recognize them as “foreign” or “nonself”, and thus to activate the body’s immune defense. If the dendritic cells have not matured properly, this can cause a failed immune response, and the immune system is unable to trigger a defense. But how do DCs drive tumor growth? Which molecular mechanisms are at work here?

Dr. Rehm and Dr. Höpken, who for years have explored the pathogenesis of lymphomas, have now investigated this question in mice with lymphoma tumors. First, they depleted the DCs and found that tumor growth was delayed a first clue that DCs are indeed associated with the growth of lymphomas. Next, the researchers wanted to know what happens when DCs come into contact with lymphoma cells. They found that after contact with lymphoma cells, the DCs increasingly secrete inflammation-promoting substances (cytokines) and growth factors.

The cytokine secretion takes place in the spleen and lymph nodes, organs that are also part of the immune system. Lymphoma cells are aberrant immune cells (B or T cells) that belong to the class of white blood cells (leukocytes). Some time ago Dr. Rehm and Dr. Höpken demonstrated that various forms of lymphoma cells settle in the lymph nodes and in the spleen where they create their own survival niche. This process is regulated by selective cytokines and growth factors that the two researchers identified a few years ago.

Survival niches for lymphoma cells

“In these niches,” Dr. Höpken said, “almost everything is already there that the lymphoma cells as malignant B cells need to survive, including blood vessels and connective tissue cells (stromal cells). The survival substances secreted by the DCs optimize the niche so that the tumors can grow better,” she explained. This also means that the DCs prevent the T lymphocytes from exercising their defensive function. Normally, healthy B or T cells settle in the respective B or T cell niches of the spleen and the lymph nodes in order to be made fit for immune defense. “What is paradoxical,” Dr. Höpken added, “is that the mouse lymphoma cells we studied – malignant B cells – found their survival niche in the T-cell zones of the lymph nodes and the spleen and not in the B-cell zones.“

After making contact with the lymphoma cells, the DCs increasingly up-regulate a transcription factor called C/EBPbeta. The cancer researcher Professor Achim Leutz (MDC) was one of the first to discover this factor in the 1990s when he was working at the Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH). This factor promotes the production of cytokines that mediate inflammation. It is now known that inflammation can lead to cancer. The influence of inflammation has been shown in cancers of the colon, stomach, breast and prostate and may also apply to liver cancer. “C/EBPbeta regulates the dendritic cells; without this transcription factor they could not secrete inflammatory cytokines. It thus also indirectly blocks apoptosis in the lymphoma cells, allowing these tumor cells to grow unchecked,” according to Dr. Rehm and Dr. Höpken.

The researchers point out that even if their model for lymphoma, which is based on a translocation and an associated overexpression of the Myc gene, is not entirely comparable to B-cell lymphomas in humans, it shows that lymphoma cells and DCs interact – a previously unknown molecular mechanism.

Significance for clinical treatment

Furthermore, the findings of the researchers may be important for clinical treatment. For several years, patients in Germany with multiple myeloma have been treated with the substance lenalidomide, a drug closely related to thalidomide that was further developed. This drug induces the down-regulation of the transcription factor C/EBPbeta, which is secreted by the cancer cells, thus causing less of it to be produced. “Considering this fact, it would be appropriate to approve the use of lenalidomide for patients with Myc B-cell lymphoma in addition to their existing cancer treatment in order to strengthen their immune defense,” the two cancer researchers suggest.

*Dendritic cell-mediated survival signals in Em-Myc B cell lymphoma depend on the transcription factor C/EBPb

Armin Rehm1,2#, Marcel Gätjen1, Kerstin Gerlach1, Florian Scholz3, Angela Mensen1,4, Marleen Gloger1, Kristina Heinig3, Björn Lamprecht1, Stephan Mathas1,2, Valérie Bégay5, Achim Leutz5, Martin Lipp3, Bernd Dörken1,2, and Uta E. Höpken3#

1Max Delbrück Center for Molecular Medicine, MDC, Department of Hematology, Oncology and Tumorimmunology, 13125 Berlin, Germany

2Charité - Universitätsmedizin Berlin, Department of Hematology and Oncology, Campus Virchow-Klinikum, 13353 Berlin, Germany

3Max Delbrück Center for Molecular Medicine, MDC, Department of Tumor Genetics and Immunogenetics; 13125 Berlin, Germany

Present address: 4Charité-Universitätsmedizin Berlin, Institute for Medical Immunology, 13353 Berlin, Germany

5Max Delbrück Center for Molecular Medicine, MDC, Department of Cell Differentiation and Tumorigenesis; 13125 Berlin, Germany

#Corresponding authors

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Barbara Bachtler
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